Pyridinone and pyridinethione derivatives having HIV inhibiting properties

ABSTRACT

The present invention is concerned among others with compounds of formula (1), the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein Q is halo, C 1-6  alkyl or C 2-6  alkenyl; X is (a-2) with q and r being O and Z being O, S or SO; R 1  is aryl; R 2  is selected from formyl; C 1-6 alkyloxycarbonylalkyl; Het 2 ; Het 2 C 1-6 alkyl, C 1-6 alkylthio; C 1-6 alkyl optionally substituted with one or two substituents each independently selected from hydroxy, and halo; R 3  is selected from formyl; C 1-6 alkyl optionally substituted with one or two C 1-6 alkyloxy; R 4  is hydrogen, with HTV inhibiting properties

The present invention is concerned with pyridinone and pyridinethione derivatives having Human Immunodeficiency Virus (HIV) replication inhibiting properties. It further relates to processes for their preparation and pharmaceutical compositions comprising them. The invention also relates to the use of said compounds in the manufacture of a medicament useful for the treatment of subjects suffering from HIV infection.

Compounds structurally related to the present compounds are disclosed in the prior art.

-   Naturforsch. B, Anorg. Chem., Org. Chem., 1983, 38 B (3), 398–403     discloses iodine, nitrogen and sulfurylides of 2-pyridones. -   Pol. J. Chem., 1979, 53 (11), 2349–2354 discloses     N-(tetrahalo-4-pyridyl) aminobenzoic acid derivatives and their use     as herbicides. -   J. Med. Chem., 1983, 26 (9), 1329–1333 discloses the synthesis of     aza analogs of lucanthone useful as antitumor and bactericidal     agents. -   WO 86/01815 discloses the synthesis of monoazodyes and their use as     dyestuffs. -   Can. J. Chem., 1980, 58 (5), 501–526 discloses the chemistry of     aurodox and related antibiotics. -   WO 97/05113 discloses 4-aryl-thio-pyridin-2(1H)-ones and their use     for treating HIV related diseases. -   WO 99/55676 discloses 3-(amino- or aminoalkyl)pyridinone or     pyridinethione derivatives and their use for the treatment of HIV     related diseases.

However their activities are still moderate and their use in human therapy also could lead to the emergence of resistant strains. The most active thiopyridinones disclosed in WO 97/05113 have a 50% inhibitory concentration of virus multiplication (IC₅₀) for nevirapine resistant strains of about 260 nM, whereas the free amino or aminoalkyl pyridinone and pyridinone derivatives disclosed in WO 99/55676 have a 50% inhibitory concentration of virus multiplication for nevirapine resistant strains of more than 10 000 nM.

The Inventors have found a new family of pyridinones and pyridinethiones derivatives which show better HIV inhibitory properties.

The present invention is concerned with compounds of formula

the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein

-   Y is O or S; -   Q is hydrogen; halo; C₁₋₆alkyl; di(C₁₋₄alkyl)amino; C₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkyl; C₁₋₆alkylthio; C₁₋₆alkylthioC₁₋₆alkyl;     C₁₋₆alkylcarbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl-S(═O)—;     C₁₋₆alkyl-S(═O)₂—; hydroxyC₁₋₆alkyl; polyhaloC₁₋₆alkyl;     C₁₋₆akyloxycarbonylC₁₋₆alkyl; C₁₋₆alkyloxycarbonylC₁₋₆alkylthio;     aminocarbonyl₆C₁₋₆alkylthio; C₁₋₆alkyloxyC₁₋₆alkyloxycarbonyl,     C₂₋₆alkenyl optionally substituted with halo, hydroxy, cyano,     formyl, —COOH, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino or aryl;     C₂₋₆alkynyl optionally substituted with halo, hydroxy, cyano,     formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino or aryl; C₃₋₆cycloalkyl     optionally substituted with C₁₋₄alkyl; cyano; carboxyl; formyl;     R⁵R⁶N—C(═O)—; R⁵R⁶N—C(═O)—C₁₋₆alkyl; N-hydroxy-imino;     N—C₁₋₄alkyloxy-imino; aryl; aryloxy; arylthio; arylC₁₋₆alkyl;     arylcarbonyl; arylC₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with     hydroxy or aryl; Het¹; Het¹oxy, Het¹thio; Het¹C₁₋₆alkyl;     Het¹carbonyl; Het¹C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl-P(OR¹⁵)₂═O or     C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O; -   X is a bivalent radical of formula     —(CH₂)_(p)—  (a-1)     or     —(CH₂)_(q)-Z-(CH₂)_(r)—  (a-2);     -   wherein p is an integer of value 1 to 5;         -   q is an integer of value 0 to 5;         -   r is an integer of value 0 to 5;         -   Z is O, S, NR⁷, C(═O), S(═O), S(═O)₂, CHOR¹³, CH═CH,             CH(NR⁷R⁸) or CF₂;     -   and wherein each hydrogen atom may be replaced by C₁₋₄alkyl or         hydroxyC₁₋₄alkyl; -   R¹ is C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkenyl, C₁₋₆alkoxy, aryl or a     monocyclic or bicyclic heterocycle selected from pyridyl, pyrimidyl,     pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl,     thiazolyl, oxazolyl, benzopyrrolyl, benzofuranyl, benzothienyl,     benzimidazolyl, benzothiazolyl, benzoxazolyl, or a radical of     formula

-    with n being an integer of 1 or 2,     -   said monocyclic or bicyclic heterocycle or said radical of         formula (b-1) or (b-2) optionally being substituted with one,         two or three substituents each independently selected from halo,         hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl,         polyhaloC₁₋₄alkyl or phenyl; -   or Q and X—R¹ may be taken together with the pyridinone to form a     tricyclic heterocycle of formula

-    with R¹⁶ and R¹⁷ being C₁₋₆alkyl or forming together ═O. -   R² and R³ each independently are selected from hydrogen; halo;     formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or     di(C₁₋₄alkyl)amino; formylamino; mercapto(C₁₋₆)alkyl; hydrazino;     R^(5a)R^(6a)N—C(═O)—; R⁹—N═C(R¹⁰)—; C₂₋₆alkenyl optionally     substituted with one or two substituents each independently selected     from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, di(C₁₋₄alkyl)carbamoyl,     [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](C₁₋₄alkyl)carbamoyl,     [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](arylC₁₋₄alkyl)carbamoyl,     di(C₁₋₄alkyloxy)(C₁₋₄alkyl)carbamoyl,     (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)aminoC₁₋₆alkyl, N-hydroxy-imino, aryl,     Het², Het²carboxamido, Het²(C₁₋₆alkyl)carbamoyl; C₂₋₆alkynyl     optionally substituted with one or two substituents each     independently selected from halo, hydroxy, cyano, formyl,     C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₁₋₆alkyloxy;     hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or     di(C₁₋₄alkyl)aminoC₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl;     Het²carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl;     aryloxy; arylC₁₋₆allyloxy; arylthio; arylC₁₋₆alkylthio; mono- or     di(aryl)amino; Het²; Het²oxy; Het²thio; Het²C₁₋₆alkyloxy;     Het²C₁₋₆alkylthio; Het²SO₂; Het²SO; mono- or di(Het²)amino;     C₃₋₆cycloalkyl; C₃₋₆cycloalkyloxy; C₃₋₆cycloalkylthio;     C₁₋₆alkylthio; hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or     di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted     with one or two substituents each independently selected from halo,     hydroxy, cyano, carboxyl, C₁₋₆alkyloxy, C₁₋₆alkylthio,     C₁₋₆alkylsulfonyl, C₁₋₆alkycarbamoylC₁₋₄alkylthio,     hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkylthio C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,     aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyloxy,     C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het², aryloxy, arylthio,     arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het²C₁₋₆alkyloxy,     Het²C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)₂-oxy, amino, mono- or     di(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)aminoC₁₋₆alkylthio,     [di(C₁₋₆alkyl)amino(C₁₋₆alkyl)](C₁₋₆alkyl)amino,     di(cyanoC₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino,     C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or     di(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino,     mono- or di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or     di(Het²C₁₋₄alkyl)amino, (Het²C₁₋₄alkyl)(C₁₋₄alkyl)amino,     (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)amino, C₃₋₆cycloalkylthio, R¹¹—(C═O)—NH—,     R¹²—NH—(C═O)—NH—, R¹⁴—S(═O)₂—NH—, C₁₋₆alkyl-P(O—R¹⁵)2=O,     C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O or a radical of formula

-    with A₁ being CH or N, and A₂ being CH₂, NR¹³, S or O, provided     that when A₁ is CH then A₂ is other than CH₂, said radical (c-1),     (c-2) and (c-3) being optionally substituted with one or two     substituents each independently selected from H, C₁₋₆alkyl,     C₁₋₆alkyloxy, hydroxy C₁₋₄alkyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkyloxycarbonylC₁₋₄alkyl, aminoC₁₋₆alkyl, C₁₋₄alkylcarbonyl,     arylcarbonyl, aryl, Het¹, Het¹-C═O)—, hydroxy, cyano,     C₁₋₄alkylcyano, CONR¹⁶R¹⁷ with R¹⁶ and R¹⁷ being independently H or     alkyl, mono or di(C₁₋₄alkyl)aminoalkyl, 4-hydroxy-4-phenyl or     4-cyano-4-phenyl; -   or R² and R³ may be taken together to form a bivalent radical of     formula     —(CH₂)_(t)—CH₂-A₃-CH₂—  (d-1)     or     —CH═CH—CH═CH—  (d-2) -   with t being an integer of 0, 1 or 2 and A₃ being CH₂, O, S, NR^(7a)     or N[C(═O)R^(8a)] and wherein each hydrogen in said formula (d-1) or     (d-2) may be substituted with halo, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl, haloC₁₋₄alkylcarbonyl or arylcarbonyl; -   R⁴ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,     C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl, amino, mono- or     di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyl or aryl; -   or R⁴ and R³ may be taken together to form a bivalent radical of     formula     —(CH₂)_(t)—CH₂-A₄-CH₂—  (e-1)     or     —CH═CH—CH═CH—  (e-2) -   with t being an integer of 0, 1 or 2 and A₄ being CH₂, O, S, NR^(7b)     or N[C(═O)R^(8b)] and wherein each hydrogen in said formula (e-1) or     (e-2) may be substituted with halo, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl, haloC₁₋₄alkylcarbonyl or arylcarbonyl; -   or X—R¹ and R² may be taken together to form a tricyclic heterocycle     of formula

-   with R¹⁶ and R¹⁷ being C₁₋₆alkyl or forming together ═O. -   R⁵ and R⁶ each independently are hydrogen, C₁₋₄alkyl or     C₁₋₄alkyloxy; -   R^(5a) and R^(6a) each independently are hydrogen; C₁₋₄alkyl     optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkylthio,     amino, mono-or di(C₁₋₄alkyl)amino or a radical of formula

-    with A₅ and A₆ each independently being CH₂, NR¹³ or O; -   R⁷, R^(7a) and R^(7b) each independently are hydrogen, formyl or     C₁₋₄alkyl; -   R⁸, R^(8a) and R^(8b) each independently are hydrogen or C₁₋₄alkyl; -   R⁹ is hydrogen, hydroxy, C₁₋₄alkyloxy, carboxylC₁₋₄alkyloxy,     C₁₋₄alkyloxycarbonyl-C₁₋₄alkyloxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy or     arylC₁₋₄alkyloxy; -   R¹⁰ is hydrogen, carboxyl or C₁₋₄alkyl; -   R¹¹ is hydrogen; C₁₋₄alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-S(═O)₂—, aryl or Het³; C₁₋₄alkyloxy;     C₂₋₄alkenyl; arylC₂₋₄alkenyl; Het³C₂₋₄alkenyl; C₂₋₄alkynyl;     Het³C₂₋₄alkynyl, arylC₂₋₄alkynyl; C₃₋₆cycloalkyl; aryl; naphthyl or     Het³; -   R¹² is C₁₋₄alkyl, arylC₁₋₄alkyl, aryl, arylcarbonyl,     C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl or     C₁₋₄alkyloxycarbonylC₁₋₄alkyl; -   R¹³ is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl; -   R¹⁴ is C₁₋₄alkyl optionally substituted with aryl or Het⁴;     polyhaloC₁₋₄alkyl or C₂₋₄alkenyl optionally substituted with aryl or     Het⁴; -   R¹⁵ is C₁₋₄ alkyl; -   Het¹ and Het² each independently are a heterocycle selected from     pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,     thiazolyl, pyridyl, pyrmidinyl, pyrazinyl, pyridazinyl,     pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,     tetrahydropyrimidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl,     piperidinyl, hexahydropyrimidinyl, piperazinyl,     hexabydropyridazinyl, morpholinyl, thiomorpholinyl triazolyl,     tetrazolyl, pyrrolyl, pyrazolyl, benzopyrrolyl, benzofuranyl,     benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,     benzotriazolyl, indolyl, indazolyl, benzodioxanyl, quinolinyl,     2-oxo-1,2-dihydro-quinolinyl, imidazopyridinyl, dihydropyrrolyl or     dihydroisoxazolyl, said heterocycle optionally being substituted     with one, two or three substituents each independently selected from     O, S, halo, formyl, amino, hydroxy, cyano, C₁₋₄alkyl,     hydroxyC₁₋₄alkyl, carboxyC₁₋₄alkyl, carbamoylC₁₋₄alkyl,     carbamoylC₁₋₄alkoxy, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl,     C₁₋₄alkyloxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl,     —OCONH₂, C₁₋₄alkoxyC₁₋₄alkyl, aryl, Het²C₁₋₄alkyl,     polyhaloC₁₋₄alkyl, C₃₋₆cycloalkyl or arylC₂₋₆alkenyl, -   Het³ is a monocyclic or bicyclic heterocycle selected from pyrrolyl,     furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,     pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl,     benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,     quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl,     tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl,     thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl,     hexahydropyridazinyl or a radical of formula

-    with A₇ or A₈ each independently being selected from CH₂ or O; each     of said monocyclic or bicyclic heterocycles may optionally be     substituted with one, two or three substituents each independently     selected from halo, hydroxy,C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; -   Het⁴ is a monocyclic heterocycle selected from pyrrolyl, furanyl,     thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl,     pyrazinyl, pyridazinyl, said heterocycle optionally being     substituted with one, two or three substituents each independently     selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; -   Het⁵ is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl,     thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl,     piperidinyl, morpholinyl or pyrrolidinyl; -   aryl is phenyl optionally substituted with one, two or three     substituents each independently selected from halo; hydroxy,     carboxyl; cyano; formyl; acetyl; nitro; amino; mono- or     di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; mono- or     di(C₁₋₄alkyl)aminocarbonylamino; C₁₋₄alkyl-S(═O)₂—NH—;     Het⁵(═S)—S—C₁₋₄alkyl; C₁₋₆alkyloxy; sulfamoyl; (C₁₋₄alkyl)sulfamoyl;     arylsulfamoyl; Het²sulfamoyl; O—P═OR¹⁵; C₁₋₆alkyl optionally     substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono-     or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkyloxy, C₂₋₆alkenyloxy, C₁₋₆alkylcarbonyloxy,     C₁₋₆alkyloxycarbonylthio, N-hydroxyimino, phenyl or Het⁵;     C₂₋₆alkenyl optionally substituted with halo, hydroxy, cyano, nitro,     formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,     N-hydroxy-imino, phenyl or Het⁵; C₂₋₆alkynyl optionally substituted     with halo, hydroxy, cyano, formyl, amino, mono- or     di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,     C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or     Het⁵; phenyl; phenyloxy; phenyl(C₁₋₄alkyl)thioC₁₋₄alkyl;     (C₃₋₆)cyclohexylthioC₁₋₄alkyl or isoxazolinyl optionally substituted     by C₁₋₄alkyloxycarbonyl or morpholinylC₁₋₄alkyl     provided that -   5,6,7,8-tetrahydro-3-iodo-4-phenoxy-1-phenyl-2(1H)quinolinone; -   3-iodo-6-methyl-4-phenoxy-2(1H)-pyridinone; -   2-[(3,5,6-trifluoro-1,2-dihydro-2-oxo-4-pyridinyl)amino]benzoic     acid; -   1,2-dihydro-6-hydroxy-2-oxo-4-(2-phenylethyl)-3-pyridinecarbonitrile; -   1,2-dihydro-6-hydroxy-2-oxo-4-(4-pyridinylmethyl)-3-pyridinecarbonitrile; -   4-[(4-bromophenyl)methoxy]-3,5-diodo-1-methyl-2(1H)-pyridinone; -   4-[(4-bromophenyl)methoxy]-1,2-dihydro-1-methyl-2-oxo-3-pyridinecarboxylic     acid; 1,2-dihydro-6-methyl-2-oxo-4-(phenylthio)-3-pyridinecarboxylic     acid and the     alkyl-4-arylthio-1,2-dihydro-5-methyl-6-methyl-2-oxo-3-pyridine     carboxylate -   3-bromo-4-[[[2-(3,4-dimethoxyphenyl)ethyl]amino]methyl-2(1H)quinolinone; -   3-iodo-7-methoxy-1-methyl-4-phenoxy-2(1H)quinolinone; -   1-ethyl-3-iodo-7-methoxy-4-phenoxy-2(1H)quinolinone; -   3-iodo-7-methoxy-4-(4-methoxyphenoxy)-1-methyl-2(1H)quinolinone; -   1-ethyl-3-iodo-7-methoxy-4-(4-methoxyphenoxy)-1-methyl-2(1H)quinolinone; -   3-iodo-7-methoxy-4-(3-methoxyphenoxy)-1-methyl-2(1H)quinolinone; -   1-ethyl-3-iodo-7-methoxy-4-(3-methoxyphenoxy)-1-methyl-2(1H)quinolinone; -   3-iodo-7-methoxy-4-phenoxy-2(1H)quinolinone; -   4-(3-chloro-4-methoxyphenoxy)-3-iodo-7-methoxy-2(1H)quinolinone; -   3-iodo-4-phenoxy-2(1H)quinolinone; -   3-iodo-4-phenoxy-1-phenyl-2(1H)quinolinone; -   3-iodo-4-(4-methylphenoxy)-2(1H)quinolinone; -   3-iodo-4-(4-methoxyphenoxy)-2(1H)quinolinone;     are not included.

As used herein C₁₋₄alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl and the like; C₁₋₆alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C₁₋₄alkyl and pentyl, hexyl, 2-methylpropyl, 2-methylbutyl and the like; C₂₋₄alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing a double bond such as ethenyl, propenyl, butenyl and the like; C₂₋₆alkenyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing at least one double bond such as the groups defined for C₂₋₄alkenyl and pentenyl, hexenyl, 2,4-hexadienyl, 1,3-butadienyl, 3-methylbutenyl and the like; C₂₋₄alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 4 carbon atoms and containing one triple bond such as ethynyl, propynyl, butynyl and the like; C₂₋₆alkynyl as a group or part of a group defines straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and containing one triple bond such as the groups defined such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, 3-methylbutynyl and the like; C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used hereinbefore, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom, a sulfonyl moiety when two of said terms are attached to a sulfur atom, a phosphonate when attached to a phosphorus atom.

The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloC₁₋₆alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C₁₋₆alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atom is attached to an alkyl group within the definition of polyhalomethyl or polyhaloC₁₋₆alkyl, they may be the same or different.

The R¹ or Het¹, Het², Het³, Het⁴ or Het⁵ radical as described above for the compounds of formula (I) may be attached to the remainder of the molecule of formula (I) through any ring carbon or heteroatom as appropriate. For example, when Het¹ is pyridyl, it may be 2-pyridyl, 3-pyridyl or 4-pyridyl.

Lines drawn into ring systems indicate that the bond may be attached to any suitable ring atom.

When any variable (e.g. aryl) occurs more than one time in any constituent, each definition is independent.

It will be appreciated that some of the compounds of formula (I) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.

The term “stereochemically isomeric forms” as used herein before defines all the possible stereoisomeric forms which the compounds of formula (I), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) and their N-oxides, salts, solvates, quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic) malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzensulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, thiehylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely the salt forms can be converted by treatment with acid into the free acid form.

The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.

The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen.

Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.

Whenever used hereinafter, the term “compounds of formula (I)” or “compounds of formula (I-a)” is meant to include also the N-oxides, the addition salts, the quaternary amines and all stereoisomeric forms.

A special group of compound contains those compounds of formula (I) wherein

-   Q is halo; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkyloxyC₁₋₆alkyl;     C₁₋₆alkylthio; C₁₋₆alkylthioC₁₋₆alkyl; C₁₋₆alkylcarbonyl;     C₁₋₆alkyloxycarbonylC₁₋₆alkyl-S(═O)—; C₁₋₆alkyl-S(═O)₂—;     hydroxyC₁₋₆alkyl; polyhaloC₁₋₆alkyl; C₁₋₆alkyloxycarbonylC₁₋₆alkyl;     C₁₋₆alkyloxyC₁₋₆alkyloxycarbonyl; C₂₋₆alkenyl optionally substituted     with halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino or aryl;     C₂₋₆alkynyl optionally substituted with halo, hydroxy, cyano,     formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino or aryl; C₃₋₆cycloalkyl     optionally substituted with C₁₋₄alkyl; cyano; carboxyl; formyl;     R⁵R⁶N—C(═O)—; R⁵R⁶N—C(═O)—C₁₋₆alkyl; N-hydroxy-imino;     N—C₁₋₄alkyloxy-imino; aryl; aryloxy; arylthio; arylC₁₋₆alkyl;     arylcarbonyl; arylC₁₋₆alkyloxycarbonyl; C₁₋₆alkyl substituted with     both hydroxy and aryl; Het¹; Het¹oxy; Het¹thio; Het¹C₁₋₆alkyl;     Het¹carbonyl; Het¹C₁₋₆alkyloxycarbonyl; C₁₋₆alkyl-P(OR¹⁵)₂═O or     C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O -   X is a bivalent radical of formula     —(CH₂)_(p)—  (a-1)     or     —(CH₂)_(q)-Z-(CH₂)_(r)—  (a-2);     -   wherein p is an integer of value 1 to 5;         -   q is an integer of value 0 to 5;         -   r is an integer of value 0 to 5;         -   Z is O, S, NR⁷, C(═O), S(═O), S(═O)₂, CHOR¹³, CH═CH,             CH(NR⁷R⁸) or CF₂;     -   and wherein each hydrogen atom may be replaced by C₁₋₄alkyl or         hydroxyC₁₋₄alkyl; -   R¹ is C₃₋₆cycloalkyl, aryl or a monocyclic or bicyclic heterocycle     selected from pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl,     thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, benzopyrrolyl,     benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl,     benzoxazolyl, or a radical of formula

-    with n being an integer of 1 or 2,     -   said monocyclic or bicyclic heterocycle or said radical of         formula (b-1) or (b-2) optionally being substituted with one,         two or three substituents each independently selected from halo,         hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl,         polyhaloC₁₋₄alkyl or phenyl; -   R² and R³ each independently are selected from hydrogen; halo;     formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or     di(C₁₋₄alkyl)amino; formylamino; R^(5a)R^(6a)N—C(═O)—; R⁹—N═C(R¹⁰)—;     C₂₋₆alkenyl optionally substituted with one or two substituents each     independently selected from halo, hydroxy, cyano, formyl,     C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₂₋₆alkynyl     optionally substituted with one or two substituents each     independently selected from halo, hydroxy, cyano, formyl,     C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₁₋₆alkyloxy;     hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or     di(C₁₋₄alkyl)aminoC₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl;     Het²carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy, aryl;     aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or     di(aryl)amino; Het²; Het²oxy; Het²thio; Het²C₁₋₆alkyloxy;     Het²C₁₋₆alkylthio; mono- or di(Het²)amino; C₃₋₆cycloalkyl;     C₃₋₆cycloalkyloxy; C₃₋₆cycloalkylthio; C₁₋₆alkylthio;     hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or     di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted     with one or two substituents each independently selected from halo,     hydroxy, cyano, C₁₋₆alkyloxy, C₁₋₆alkylthio, hydroxyC₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy,     aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyloxy,     C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het², aryloxy, arylthio,     arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het²C₁₋₆alkyloxy,     Het²C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)₂-oxy, amino, mono- or     di(C₁₋₆alkyl)amino, C₁₋₆alkyloxy-carbonylamino,     C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or     di(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino,     mono- or di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono or     di(Het²C₁₋₄alkyl)amino, R¹¹—(C═O)—NH—, R¹²—NH—(C═O)—NH—,     R¹⁴—S(═O)₂—NH—, C₁₋₆alkyl-P(O—R¹⁵)₂═O, C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O     or a radical of formula

-    with A₁ being CH or N, and A₂ being CH₂, NR¹³, S or O, provided     that when A₁ is CH then A₂ is other than CH₂, said radical (c-1) and     (c-2) being optionally substituted with one or two substituents each     independently selected from H, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy     C₁₋₄alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₄alkyl,     aminoC₁₋₆alkyl, carbonyl, hydroxy, cyano, CONR¹⁶R¹⁷ with R¹⁶ and R¹⁷     being independently H or alkyl, mono or di(C₁₋₄alkyl)aminoalkyl,     4-hydroxy-4-phenyl or 4-cyano-4-phenyl; -   or R² and R³ may be taken together to form a bivalent radical of     formula     —(CH₂)_(t)—CH₂-A₃-CH₂—  (d-1)     or     —CH═CH—CH═CH—  (d-2) -   with t being an integer of 0, 1 or 2 and A₃ being CH₂, O, S, NR^(7a)     or N[C(═O)R^(8a)] and wherein each hydrogen in said formula (d-1) or     (d-2) may be substituted with halo, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl, haloC₁₋₄alkylcarbonyl or arylcarbonyl; -   R⁴ is hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyl,     C₁₋₆alkylcarbonyloxyC₁₋₆alkyl, C₂₋₆alkenyl, amino, mono- or     di(C₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyl)aminoC₁₋₄alkyl or aryl; -   or R⁴ and R³ may be taken together to form a bivalent radical of     formula     —(CH₂)_(t)—CH₂-A₄-CH₂—  (e-1)     or     —CH═CH—CH═CH—  (e-2) -   with t being an integer of 0, 1 or 2 and A₄ being CH₂, O, S, NR^(7b)     or N[C(═O)R^(8b)] and wherein each hydrogen in said formula (e1) or     (e-2) may be substituted with halo, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl, haloC₁₋₄alkylcarbonyl or arylcarbonyl; -   R⁵ and R⁶ each independently are hydrogen, C₁₋₄alkyl or     C₁₋₄alkyloxy, -   R^(5a) and R^(6a) each independently are hydrogen; C₁₋₄alkyl     optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkylthio,     amino, mono- or di(C₁₋₄alkyl)amino; or a radical of formula

-    with A₅ and A₆ each independently being CH₂, NR¹³ or O; -   R⁷, R^(7a) and R^(7b) each independently are hydrogen, formyl or     C₁₋₄alkyl; -   R⁸, R^(8a) and R^(8b) each independently are hydrogen or C₁₋₄alkyl; -   R⁹ is hydrogen, hydroxy, C₁₋₄alkyloxy, carboxylC₁₋₄alkyloxy,     C₁₋₄alkyloxycarbonyl-C₁₋₄alkyloxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy or     arylC₁₋₄alkyloxy; -   R¹⁰ is hydrogen, carboxyl or C₁₋₄alkyl; -   R¹¹ is hydrogen; C₁₋₄alkyl optionally substituted with cyano,     C₁₋₄alkyloxy, C₁₋₄alkyl-S(═O )₂—, aryl or Het³; C₁₋₄alkyloxy,     C₂₋₄alkenyl; arylC₂₋₄alkenyl; Het³C₂₋₄alkenyl; C₂₋₄alkynyl;     Het³C₂₋₄alkynyl, arylC₂₋₄alkynyl; C₃₋₆cycloalkyl; aryl; naphthyl or     Het³; -   R¹² is C₁₋₄alkyl, arylC₁₋₄alkyl, aryl, arylcarbonyl,     C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl, or     C₁₋₄alkyloxycarbonylC₁₋₄alkyl; -   R¹³ is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl; -   R¹⁴ is C₁₋₄alkyl optionally substituted with aryl or Het⁴;     polyhaloC₁₋₄alkyl or C₂₋₄alkenyl optionally substituted with aryl or     Het⁴; -   R¹⁵ is C₁₋₄alkyl; -   Het¹ and Het² each independently are a heterocycle selected from     pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl,     pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl,     tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl,     thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl,     hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl,     benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl or     2-oxo-1,2-dihydro-quinolinyl, said heterocycle optionally being     substituted with one, two or three substituents each independently     selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; -   Het³ is a monocyclic or bicyclic heterocycle selected from pyrrolyl,     furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl,     pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl,     benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,     quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl,     tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl,     thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl,     hexahydropyridazinyl or a radical of formula

-    with A₇ or A₈ each independently being selected from CH₂ or O; each     of said monocyclic or bicyclic heterocycles may optionally be     substituted with one, two or three substituents each independently     selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; -   Het⁴ is a monocyclic heterocycle selected from pyrrolyl, furanyl,     thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl,     pyrazinyl, pyridazinyl, said heterocycle optionally being     substituted with one, two or three substituents each independently     selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy,     C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; -   Het⁵ is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl,     thienyl, furanyl, imidazolyl, thiazolyl or oxazolyl; -   aryl is phenyl optionally -substituted with one, two or three     substituents each independently selected from halo; hydroxy;     carboxyl; cyano; formyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino;     C₁₋₄alkylcarbonylamino; mono- or di(C₁₋₄alkyl)aminocarbonylamino;     C₁₋₄alkyl-S(═O)₂—NH—; C₁₋₆alkyloxy; C₁₋₆alkyl optionally substituted     with halo, hydroxy, cyano, formyl, amino, mono- or     di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,     C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino,     phenyl or Het⁵; C₂₋₆alkenyl optionally substituted with halo,     hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl,     C₁₋₆alkylcarbonyloxy, N-hydroxy-imino phenyl or Het⁵; C₂₋₆alkynyl     optionally substituted with halo, hydroxy, cyano, formyl, amino,     mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy,     C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or     Het⁵; phenyl or phenyloxy;

A special group of compound contains those compounds of formula (I) wherein

-   Q is halo, C₁₋₆alkyl or C₂₋₆alkenyl; -   X is (a-2) with q and r being 0 and Z being O, S or SO; -   R₁ is aryl; -   R₂ is selected from formyl; C₁₋₆alkyloxycarbonylalkyl; Het²;     Het²C₁₋₆alkyl; C₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with     one or two substituents each independently selected from hydroxy or     halo; -   R₃ is selected from formyl; C₁₋₆alkyl optionally substituted with     one or two C₁₋₆alkyloxy; -   R⁴ is hydrogen.

Particular compounds are those compounds of formula (I) wherein Q is iodo.

Preferred compounds are those compounds of formula (I) wherein Q is iodo, X—R₁ is a 3,5-dimethylphenylthio or a 3,5-dimethylphenyloxy and R₂ is a hydroxymethyl or a N-morpholinomethyl or a 3-phenylpropyl or a furan-2-yl-methylthiomethyl. Also preferred compounds are those compounds of formula (I) wherein Q is iodo, X—R₁ is a 3-(2-cyano-vinyl)-5-iodophenyloxy or 5-bromo-3-(2-cyano-vinyl) and R₂ is ethyl.

Most preferred compounds are compounds n° 242, 255, 43, 264, 124, 249, 298, 326, 133, 241, 253, 306, 328, 46, 105, 234, 254, 256, 272, 284, 296, 319, 83, 88, 108, 109, 115, 277, 286, 299, 45, 85, 86, 231, 244, 297, 250, 257, 307, 324, 81, 92, 140, 143, 217, 221, 230, 232, 245, 309, 321, 322, 31, 218, 222, 314, 8, 99, 121, 219, 233, 280, 551, 470, 375, 483, 547, 606, 618, 662, 694, 700, 709 and 713 of table 1.

The present invention also relates to a method of treating warm-blooded animals suffering from HIV infection. Said method comprises the administration of the therapeutically effective amount of a compound of formula (I) or any sub group thereof, a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof in admixture with a pharmaceutical carrier.

The compounds of formula (I) can be prepared according to art-known procedures.

In general, compounds of formula (I) wherein X is an oxygen and R₁ a 3,5-dimethylphenyl, said compound being represented by formula (I-a) can be prepared by reacting an intermediate of formula (II) with a derivative of formula (III)

In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.

The compounds of formula (I) wherein X is a sulphur, said compound being represented by formula (I-b) can be prepared by reacting an intermediate of formula (IV) with a derivative of formula (V) in an appropriate solvent such as for example methanol, ethanol, propanol, butanol, dioxane, tetrahydrofurane, 2-methoxyethylether or toluene, and the like. This reaction can be performed at a temperature comprised between 20 and 130° C.

The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.

The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization of chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.

An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography using a chiral stationary phase.

Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.

The compounds of formula (I) as prepared in the hereinabove described processes may be synthesized as a mixture of stereoisomeric forms, in particular in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.

It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C₁₋₆alkyl or benzyl esters.

The protection and deprotection of functional groups may take place before or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups in Organic Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in Organic Synthesis’ 2^(nd) edition, T W Greene & P G M Wutz, Wiley Interscience (1991).

The compounds of the present invention show antiretroviral properties, in particular against Human Immunodeficiency Virus (HIV), which is the aetiological agent of Acquired Immune Deficiency Syndrome (AIDS) in humans. The HIV virus preferentially infects human T-4 cells and destroys them or changes their normal function, particularly the coordination of the immune system. As a result, an infected patient has an everdecreasing number of T-4 cells, which moreover behave abnormally. Hence, the immunological defense system is unable to combat infections and neoplasms and the HIV infected subject usually dies by opportunistic infections such as pneumonia, or by cancers. Other conditions associated with HIV infection include thrombocytopaenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as progressive dysarthria, ataxia and disorientation. HIV infection further has also been associated with peripheral neuropathy progressive generalized lymphadenopathy (PGL) and AIDS-related complex (ARC).

The present compounds also show activity against HIV-1 strains that have acquired resistance to art-know non-nucleoside reverse transcriptase inhibitors. They also have little or no binding affinity to human α-1 acid glycoprotein.

Due to their antiretroviral properties, particularly their anti-HIV properties, especially their anti-HIV-1-activity, the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the enzyme reverse transcriptase. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.

The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1.

The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid sugars, kaolin, lubricants, binders, disintegrating agent and the like in the case of powders pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the list advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

To aid solubility of the compounds of formula (I), suitable ingredients, e.g. cyclodextrins, may be included in the compositions. Appropriate cyclodextrins are α, β, γ-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C₁₋₆alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated β-CD; hydroxyC₁₋₆alkyl, particularly hydroxyethyl, hydroxy-propyl or hydroxybutyl; carboxyC₁₋₆alkyl, particularly carboxymethyl or carboxy-ethyl; C₁₋₆alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are β-CD, randomly methylated β-CD, 2,6-dimethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxyethyl-β-CD, 2-hydroxypropyl-β-CD and (2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxypropyl-β-CD (2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.

The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.

Other suitable compositions for oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (I) and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.

Said particles consist of a solid dispersion comprising a compound of formula (I) and one or more pharmaceutically acceptable water-soluble polymers. The preferred technique for preparing solid dispersions is the melt-extrusion process comprising the following steps:

-   -   a) mixing a compound of formula (I) and an appropriate         water-soluble polymer,     -   b) optionally blending additives with the thus obtained mixture,     -   c) heating the thus obtained blend until one obtains a         homogenous melt,     -   d) forcing the thus obtained melt through one or more nozzles;         and     -   e) cooling the melt till it solidifies.

The solid dispersion product is milled or ground to particles having a particle size of less than 1500 μm, preferably less than 400 μm, more preferably less than 250 μm and most preferably less than 125 μm.

The water-soluble polymers in the particles are polymers that have an apparent viscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v), of 1 to 5000 mPa.s, more preferably of 1 to 700 mPa.s, and most preferred of 1 to 100 mPa.s. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkyl-celluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts and esters thereof, methacrylate copolymers, polyvinylalcohol, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are Eudragit E® (Röhm GmbH, Germany) and hydroxypropyl methylcelluloses.

Also one or more cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly α, β, γ-cyclodextrins or the pharmaceutically acceptable derivatives thereof.

Substituted cyclodextrins which can be used include polyethers described in U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C₁₋₆alkyl, hydroxyC₁₋₆alkyl, carboxy-C₁₋₆alkyl or C₁₋₆alkyloxycarbonylC₁₋₆alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C₁₋₃alkyl, hydroxyC₂₋₄alkyl or carboxyC₁₋₂alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.

Of particular utility are the β-cyclodextrin ethers, e.g. dimethyl-β-cyclodextrin as described by M. Nogradi (Drugs of the Future, (1984) Vol. 9, No. 8, p. 577–578) and polyethers, e.g. hydroxypropyl β-cyclodextrin and hydroxyethyl β-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for example be formed from the reaction between β-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.

A more novel type of substituted cyclodextrins is sulfobutylcyclodextrines.

The ratio of the compound of formula (I) over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of the compound of formula (I) over cyclodextrin range from about 1/10 to 10/1. More interesting ratios range from about 1/5 to 5/1.

It may further be convenient to formulate the compounds of formula (I) in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the compound of formula (I) but do not chemically bond to said compound.

Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds of formula (I) involves a pharmaceutical composition whereby the compounds of formula (I) are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.

Said beads comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and a compound of formula (I) and a seal-coating polymer layer.

Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.

Those of skill in the treatment of HIV-infection could determine the effective daily amount from the test results presented here. In general, it is contemplated that an effective daily amount would be from 0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose at two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, the weight and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased of the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines and are not intended to limit the scope or use of the invention to any extent.

Also, the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other antiretroviral compounds may be known antiretroviral compounds such as nucleoside reverse transcriptase inhibitors, e.g. zidovudine (3′-azido-3′-deoxythymidine; AZT), didanosine (dideoxy inosine; ddI), zalcitabine (dideoxycytidine; ddC) or lamivudine (3′-thia-2′-3′-dideoxycytidine; 3TC) and the like; non-nucleoside reverse transcriptase inhibitors such as suramine, pentamidine, thymopentin, castanospermine, efavirenz, rescriptor (BHAP derivative), dextran (dextran sulfate), foscarnet-sodium (trisodium phosphono formate), nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6Hdipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one), tacrine (tetrahydroaminoacridine) and the like; compounds of the TIBO (tetrahydro-imidazo[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and thione)-type e.g. (S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepine-2(1H)-thione compounds of the α-APA (α-anilino phenyl acetamide) type e.g. α-[(2-nitro-phenyl)amino]-2,6-dichloro-benzene-acetamide and the like; TAT-inhibitors, e.g. RO-5-3335 and the like; protease inhibitors e.g. indinavir, ritanovir, saquinovir, ABT-378 and the like; fusion inhibitors; integrase inhibitors; or immunomodulating agents, e.g. levamisole and the like. The compound of formula (I) can also be combined with another compound of formula (I).

The following examples are intended to illustrate the present invention. The numbers under the formulas correspond to the numbers in the table (I).

EXAMPLE 1 Ethyl 2-azido-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (compound 106)

2-chloro-4-hydroxy-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester (intermediate 1) was obtained as described by J. A. Elvidge and N. A. Zaidi (J. Chem. Soc., (1968), 17, 2188) and dichloro-3,5-dimethyliodobenzene (intermediate 2) as described by H. J. Lucas, E. R. Kennedy, Org. Synth. (1955) Vol-III, 482–483.

1.1.: Ethyl 2-chloro-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (intermediate 3)

Intermediate 2 (0.73 g, 2.2 mmol) was suspended in 10 ml of water containing sodium carbonate (0.24 g, 2.2 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of intermediate 1 (0.44 g, 2 mmol) in 10 ml of water containing also sodium carbonate (0.22 g; 2 mmol) was added. After stirring for one hour at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in diglyme (5 ml). After heating at 100° C. for 10 min., the solvent was removed in vacuo. Purification by flash chromatography (SiO₂, CH₂Cl₂/ethanol 98:2) gave the titled compound (0.6 g, 67%) as yellow microcrystals, m.p. 180–182° C.

1.2.: Ethyl 2-azido-4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-6-oxo-3-pyridinecarboxylate (compound 106)

Sodium azide (0.20 g, 3.12 mmol) was added to a solution of intermediate 3 (0.50 g, 1.56 mmol) in DMSO (5 ml), and the mixture was heated at 50° C. for 5 hours Reaction mixture was partitioned between water (30 ml) and ethyl acetate (40 ml). The organic layer was dried over magnesium sulfate and concentred. Flash chromatography (SiO₂, CH₂Cl₂/ethanol 95:5) gave the desired product (0.49 g, 70%) as a white solid, m.p.=216–218° C.

EXAMPLE 2 4-[3,5-dimethylphenyl)-sulfinyl]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (compound 108)

4-[3,5-dimethylphenyl)-thio]-5-ethyl-6-methyl-2(1H)-pyridinone (intermediate 4) was obtained as described by Dollé et al. (J. Med. Chem., (1995), 38, 4679–4686).

2.1.: 4-[3,5-dimethylphenyl)-thio]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (intermediate 5)

The intermediate 4 (273 mg, 1 mmol) was dissolved in acetic acid (4 ml) and ethyl acetate (4 ml). At room temperature and in the dark N-iodosuccinimide (225 mg; 1 mmol) was added in one portion. After 4 hours under stirring at room temperature, the mixture was poured into water (15 ml) and the pH of the solution was adjusted to 7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3×30 ml) were washed with brine (10 ml), dried over magnesium sulfate and evaporated to give a gum. It was then purified by flash chromatography on silica gel column with CH₂Cl₂-ethanol (98:2) as the eluent to give the main fraction containing the titled compound which was recristallized from ethanol furnishing the pure intermediate 5 as yellow microcrystals (122 mg; 51%), m.p.=252° C.

2.2.: 4[-3,5-dimethylphenyl)-sulfinyl]-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (compound 108)

m-chloroperbenzoic acid and water (70%, 123 mg; 0.5 mmol) in chloroform (15 ml) was dried over magnesium sulfate and filtered. To this solution at 0° C. was added the intermediate 5 (200 mg; 0.5 mmol) and the mixture was kept under stirring for 1 hour. A saturated solution of sodium carbonate (5 ml) was added and the combined organic layers obtained by extraction with CH₂Cl₂ (3×30 ml) were dried over magnesium sulfate and evaporated. The residue obtained was then chromatographed (SiO₂, CH₂Cl₂/ethanol 98:2) to give the titled compound (113 mg; 50%).

1H NMR. (200 MHz, CDCl3), d: 0.66 (t, 3H, CH3-CH2, J=6.9 Hz); 2.20–2.90 (m, 11H, CH3-6,3′,5′, CH2CH3); 7.08 (s, 1H, H-4′); 7.25 (s, 2H, H-2′,6′); 12.9 (s, 1H, NH).

EXAMPLE 3 4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxaldehyde (compound 269)

Ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylate (intermediate 6) was described by E. Knoevenagel and A. Fries (Ber., (1898), 31, 768).

3.1.: Ethyl 4-hydroxy-5-hydroxymethyl-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarboxylate (intermediate 7)

The mixture of intermediate 6 (1.8 g; 9.1 mmol), Na₂CO₃ (970 mg; 9.1 mmol) and water (30 ml) was heated in an oil bath at 90° C. Three portions of 37% formaldehyde solution in water (1.46 ml; 18.2 mmol each) were added every 45 min. The homogeneous mixture obtained was kept at the same temperature for 30 min. further and the oil bath was removed. When the internal temperature reaches 60° C., ethyl acetate (40 ml) and acetic acid (1.8 ml) were added and after extraction with hot ethyl acetate (4×40 ml) the organic layer was evaporated under reduced pressure. The residue was then purified by flash chromatography on a silica gel column with CH₂Cl₂/ethanol (95:5) as the eluent to give the expected intermediate 7 (830 mg; 40%), m.p.=262–265° C.

3.2.: Ethyl 5-formyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydro-3-pyridine-3-carboxylate (intermediate 8)

To a stirred solution of intermediate 7 (500 mg; 2.2 mmol) in CH₂Cl₂ (80 ml) was added at reflux MnO₂ (4 g; 46 mmol) and the reflux was maintained for 50 hours. The hot mixture was filtered off, the solid was washed successively with hot methanol (3×50 ml) and hot ethyl acetate (3×50 ml). The solvents were evaporated and the solid residue obtained was then purified by flash chromatography on a column of silica gel with CH₂Cl₂/ethanol (98:2) as the eluent to give the intermediate 8 (420 mg; 85%); m.p.=248–250° C.

3.3.: 4-hydroxy-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxaldehyde (intermediate 9)

To a solution of intermediate 8 (350 mg; 1.5 mmol) in 1,4-dioxane (15 ml) was added water (7.6 ml) and 1N HCl (2.4 ml) and the mixture was heated under reflux for 24 hours. The hot solution was extracted with ethyl acetate (3×30 ml) and the solvent was removed under reduced pressure furnishing the titled intermediate 9 as yellow microcrystals (110 mg; 47%); m.p.>260° C. This compound was used for the next step without any further purification.

3.4.: 4-(3,5-dimethylphenoxy)-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxaldehyde (compound 269)

Intermediate 2 (1.31 g, 4.32 mmol) was suspended in 25 ml of water containing sodium carbonate (0.46 g, 4.32 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of intermediate 9 (0.55 g, 3.6 mmol) in 25 ml of water containing also sodium carbonate (0.38 g; 3.6 mmol) was added. After stirring for 1 hour at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in dimethylformamide (15 ml). After heating under reflux for 1 h the solvent was removed in vacuo. Purification by flash chromatography (SiO₂, CH₂Cl₂/EtOH 95:5) gave the titled compound (1.01 g, 73%) as yellow microcrystals, m.p.>260° C.

EXAMPLE 4 4-(3,5-dimethylphenoxy)-5-(hydroxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 257)

To a stirred solution of compound 269 (500 mg; 1.3 mmol) in methanol (50 ml) was added NaBH₄ (350 mg; 9.2 mmol) in small portions for a period of 10 min. After 1 hour on stirring at room temperature, water (20 ml) and a solution 10% potassium carbonate (30 ml) were added. The mixture was extracted with ethyl acetate (3×60 ml) and the organic layer was washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure giving colorless microcrystals which correspond to the titled compound (490 mg; 97%) m.p.=248–250° C.

EXAMPLE 5 5-(chloromethyl)-4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-2(1H)-pyridinone (compound 125)

The heterogeneous solution of compound 257 (450 mg; 1.2 mmol) in CH₂Cl₂ (30 ml) became homogeneous mixture by addition at room temperature of SOCl₂ (2.6 ml). After 2 hours on stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected compound 125 in quantitative yield (470 mg); m.p.=256–258° C. This compound was used for the next step without any further purification.

EXAMPLE 6 4-(3,5-dimethylphenoxy)-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 255)

A solution of compound 125 (60 mg; 0.15 mmol) in absolute ethanol (5 ml) and potassium carbonate (60 mg; 0.44 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, water (5 ml) was added and the mixture was extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (5 ml), dried over magnesium sulfate and the solvent was removed. The colorless solid residue was then purified by flash chromatography on a silica gel column with CH₂Cl₂/ethanol (98:2) as the eluent to give the titled compound 255 (59 mg; 95%); m.p.=234–236° C.

EXAMPLE 7 4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-6-methyl-2(1H)-pyridinone (compound 258)

This compound was prepared starting from the 5-ethyl-6-methyl-4-hydroxypyridin-2(1H)-one (intermediate 10) which was obtained as described by Dollé et al. (J. Med. Chem., (1995), 38, 4679–4686).

Intermediate 2 (3.75 g; 12.4 mmol) was suspended in water (50 ml) containing sodium carbonate (1.31 g; 12.4 mmol) and stirred for 30 min at room temperature. To this mixture a solution intermediate 10 (1.9 g; 12.4 mmol) in water (50 ml) containing also sodium carbonate (1.31 g; 12.4 mmol) was added. After stirring for 1 hour at 20° C. the precipitate was filtered off, washed with water, dried under vacuum at room temperature and suspended in dimethylformamide (20 ml). The mixture was refluxed for 1 hour. The solvent was removed in vacuo. Purification by flash chromatography (SiO₂, CH₂Cl₂/Et OH 98:2) gave the titled compound (4.3 g; 90%) as colorless microcrystals; m.p.=240° C.

EXAMPLE 8 4-(3,5-dimethylphenoxy)-3-ethenyl-5-ethyl-6-methyl-2(1H)-pyridinone (compound 234)

Compound 258 (300 mg, 0.1783 mmol) and palladium tetrakistriphenylphosphine (45 mg, 5% mol) were dissolved in toluene (6 ml). Tributyl(vinyl)tin (358 mg, 0.94 mmol) was added at room temperature. The mixture was refluxed for 12 hours. Water (8 ml) was added and the aqueous layer was extracted with dichloromethane and dried over magnesium sulfate. The solvent was removed under vacuum and the residue was purified by flash chromatography (SiO₂, CH₂Cl₂/ethanol 98:2) to give the titled compound 234 as colorless microcrystals (87 mg, 39%); m.p.=200° C.

EXAMPLE 9 4-(3,5-dimethylphenoxy)-3,5-diethyl-6-methyl-2(1H)-pyridinone (compound 231)

Compound 234 (90 mg, 0.318 mmol) was dissolved in absolute ethanol (10 ml). The catalyst palladium on carbon 10% (44 mg) was added. The mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. The catalyst was filtered off and the solvent was evaporated under vacuum. The residue was purified by flash chromatography (SiO₂, CH₂Cl₂/ethanol 98:2) to give the desired compound as colorless microcrystals (60 mg, 66%);, m.p.=180° C.

EXAMPLE 10 4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 86)

10.1. Ethyl 4-hydroxy-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (intermediate 12)

This compound was prepared starting from the di-(2,4,6-trichlorophenyl)malonate (intermediate 11) which was obtained as described by Kappe, Th., (Mh. Chem. (1967), 98, 874).

A solution of ethyl 3-aminocrotonate (12.6 g, 97.5 mmol) and of intermediate 11 in diglyme (400 ml) was heated at 100° C. for 3 hours during which the product separated out. After cooling, diethylether (1.5 l) was added and the desired intermediate 12 was filtered (14.2 g, 75%). m.p. 243–245° C.

10.2.: Ethyl 4-chloro-2-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (intermediate 13)

To a solution of intermediate 12 (2 g; 10 mmol) and benzyltriethylammonium chloride (9.1 g; 40 mmol) in acetonitrile (40 ml) was added in one portion phosphorus oxychloride (2.2 ml; 24 mmol). The obtained mixture was stirred at room temperature under nitrogen atmosphere for 5 min. and heated under reflux for 2 hours. After evaporation of the solvent, cool water (40 ml) was added and the mixture was stirred for 0.5 hour. Extraction with CH₂Cl₂ followed by a silica gel column chromatography using CH₂Cl₂/ethanol (99:1) as eluent gave i) ethyl 2,4-dichloro-6-methylpyridin-5-ylcarboxylate (1.7 g; 72%) (which can be transformed into the intermediate 13 and ii) intermediate 13 (506 mg; 24%) m.p.=161–163° C.

10.3.: Ethyl 4-[(3,5-dimethylphenyl)-thio]-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylate (intermediate 14)

A mixture of the intermediate 13 (1.2 g; 5.6 mmol) in ethanol (15 ml), triethylamine (1.5 ml) and 3,5-dimethylthiophenol (1.45 ml; 11 mmol) was heated under reflux for 16 hours. After evaporation under reduced pressure, diethylether (50 ml) was added and the precipitate was filtered off. The intermediate 14 was obtained (1.42 g; 80%) as a colorless solid m.p.=233–235° C.

10.4.: 4-[(3,5-dimethylphenyl)-thio]-5-(hydroxymethyl)-6-methyl-2(1H)-pyridinone (intermediate 15)

Under nitrogen atmosphere, the intermediate 14 (500 mg; 1.6 mmol) was suspended in dry tetrahydrofurane (20 ml) and LiAlH₄ (120 mg; 3.2 mmol) was added at 0° C. The mixture was stirred at room temperature for 18 hours and poured in ethyl acetate (50 ml) at 0° C. and a solution 10% H₂SO₄ (100 ml) was added dropwise. The mixture was extracted with ethyl acetate (2×100 ml) and the organic layer was removed under reduced pressure giving the intermediate 15 (310 mg; 71%) m.p.=268–270° C.

10.5.: 4-[(3,5-dimethylphenyl)-thio]-5-(chloromethyl)-6-methyl-2(1H)-pyridinone (intermediate 16)

A suspension of intermediate 15 (275 mg; 1 mmol) in dichloromethane (10 ml) became homogeneous by addition of SOCl₂ (2.3 ml) at room temperature. After 2 hours of stirring at room temperature, all the volatiles were removed under reduced pressure giving a yellow solid which corresponds to the expected intermediate 16 in quantitative yield (294 mg).

This compound was used for the next step without further purification.

10.6.: 4-[(3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-6-methyl-2(1H)-pyridinone (intermediate 17)

A solution of intermediate 16 (250 mg; 0.85 mmol) in absolute ethanol (10 ml) and triethylamine (0.24 ml) was heated at 50° C. for 18 hours. After evaporation under reduced pressure the residue was purified by flash chromatography on a silica gel column with CH₂Cl₂/ethanol (99:1) as the eluent to give the titled intermediate 17 (243 mg; 94%) m.p.=203–205° C.

10.7.: 4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 86)

The intermediate 17 (100 mg; 0.33 mmol) was dissolved in acetic acid (2 ml) and ethyl acetate (2 ml). At room temperature and in the dark N-iodosuccinimide (75 mg; 0.33 mmol) was added in one portion. After 2.5 h under stirring at room temperature, the mixture was poured into water (5 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia. The combined organic layers obtained by extraction with CH₂Cl₂ (3×10 ml) were washed with water (15 ml), dried over magnesium sulfate and evaporated to give a solid residue. It was then chromatographed on silica gel column with CH₂Cl₂/ethanol (99:1) as the eluent to give the titled compound 86 as colorless microcrystals (96 mg; 68%) m.p.=220–222° C.

EXAMPLE 11 3-bromo-4-[3,5-dimethylphenyl)-thio]-5-(ethoxymethyl)-6-methyl-2(1H)-pyridinone (compound 85)

The intermediate 17 (50 mg; 0.16 mmol) was dissolved in acetic acid (3 ml) and ethyl acetate (3 ml). At room temperature and in the dark N-bromosuccinimide (29 mg; 0.16 mmol) was added in one portion. After 30 min. under stirring at room temperature, the mixture was poured into water (10 ml) and the pH of the solution was adjusted to ca.7 with 28% ammonia. The combined organic layers obtained by extraction with ethyl acetate (3×15 ml) were dried over magnesium sulfate and evaporated to give a solid residue. It was then purified by flash chromatography on silica gel column with CH₂Cl₂/ethanol (99:1) as the eluent to give the titled compound 85 as colorless microcrystals (48 mg; 76%) m.p.=183–184° C.

EXAMPLE 12 Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxylate (compound 71)

12.1.: Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-2-methyl-1-6-oxo-3-pyridinecarboxylate (intermediate 18)

3,5-dimethylthiophenol (0.69 ml; 5.1 mmol) was added to a mixture of intermediate 13 (1 g; 4.6 mmol) in triethylamine (1 ml) and ethanol (10 ml). The mixture was stirred and refluxed then brought to room temperature and poured out into water. The precipitate was filtered. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried to yield (1.2 g; 80%) of intermediate 18; m.p.=230° C.

12.2.: Ethyl 4-[3,5-dimethylphenyl)-thio]-1,6-dihydro-5-iodo-2-methyl-6-oxo-3-pyridinecarboxylate (compound 71)

N-iodosuccinimide (0.085 g; 0.4 mmol) was added at room temperature to a solution of intermediate 18 (0.1 g; 0.3 mmol) in ethyl acetate (0.3 ml) and acetic acid (0.3 ml) under nitrogen. The mixture was stirred 48 hours in darkness. The solvent was evaporated. The residue was purified by column chromatography over Kromasil® (CH₂Cl₂; 100). Two fractions were collected and the solvent was evaporated to give 0.052 g of a compound which was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield (32 mg; 23%) of compound 71; m.p.=210° C.

EXAMPLE 13 4-[3,5-dimethylphenyl)-thio]-5-(hydroxymethyl)-3-iodo-6-methyl-2(1H)-pyridinone (compound 61)

Diisobutylaluminium hydride (20 wt. % solution in toluene) (0.75 ml; 0.9 mmol) was added at −70° C. to a mixture of compound 71 (0.1 g; 0.2 mmol) in toluene (10 ml). The mixture was stirred at 0° C. for 1 hour, poured out into water and extracted with ethyl acetate. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield (56 mg; 70%) of compound 61; m.p.=240° C.

EXAMPLE 14 5-(chloromethyl)-4-[-3,5-dimethylphenyl)-thio]-3-iodo-6-methyl-2(1H)-pyridinone (compound 60)

SOCl₂ (0.9 ml; 12.3 mmol) was added dropwise at 0° C. to a solution of compound 61 (0.8 g; 1.9 mmol) in CH₂Cl₂ (90 ml). The mixture was stirred at room temperature overnight and evaporated till dryness. The residue was taken up in CH₂Cl₂ and evaporated (3 times) to yield 0.7 g (89%) m.p.=218° C. The product was used without further purification in the next reaction step.

EXAMPLE 15 4-[3,5-dimethylphenyl)-thio]-5-[(ethylthio)methyl]-3-iodo-6-methyl-2(1H)-pyridinone (compound 45)

A mixture of compound 60 (0.1 g; 0.2 mmol) and ethanethiol (0.0361 ml; 0.5 mmol) in triethylamine (0.1 ml) and ethanol (2 ml) was stirred and refluxed for 4 hours. The solvent was evaporated. The residue (0.06 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH; 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.02 g) was crystallized from diisopropylether. The precipitate was filtered off and dried to yield 0.018 g (17%); m.p.=210° C.

EXAMPLE 16 4-[(3,5-dimethylphenyl)-thio]-3-iodo-6-methyl-5-morpholinomethyl-1H-pyridin-2-one (compound 43)

A mixture of compound 60 (0.05 g; 0.1 mmol), morpholine (0.02 ml; 0.0002 mol) and K₂CO₃ (0.082 g; 0.6 mmol) in acetonitrile (2 ml; 0.6 mmol) was stirred at 50° C. in a sealed tube for 2 hours, poured out into water and extracted with ethylacetate. The solvent was evaporated. The residue was crystallized from diisopropyl ether. The precipitate was filtered off and dried. The residue (0.057 g) was crystallized from isopropanol. The precipitate was filtered off and dried to yield 0.041 g (73%), m.p.=230° C.

EXAMPLE 17 6-(diethoxymethyl)-4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-2(1H)-pyridinone (compound 134)

17.1.: 6-(diethoxymethyl)-5-ethyl-4-hydroxy-2H-pyran-2-one (intermediate 19)

A solution of sodium hydride (60% dispersion in mineral oil) in tetrahydrofurane (500 ml) was cooled at 0° C. under nitrogen. 3-oxo-hexanoic-acid ethyl ester (25 g; 158 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 minutes. Butyllithium 1.6 M (99 ml; 158 mmol) was added dropwise and the mixture was stirred at 0° C. for 1 hour. Diethoxy-acetic acid ethyl ester (27.8 g; 0.178 mol) was added drop wise and the mixture was stirred at 0° C. for 1 hour. Hydrochloric acid 12 N (50 ml) was added and the mixture was stirred at room temperature for 1 hour and extracted with diethyl ether to yield 20 g (53%) of intermediate 19. The product was used without further purification in the next reaction step.

17.2.: 6-(diethoxymethyl)-5-ethyl-4-hydroxy-2(1H)-pyridinone (intermediate 20)

A mixture of intermediate 19 (20 g; 82 mmol) in CH₃OH/NH₃ (150 ml) was stirred at 60° C. for 4 hours, evaporated till dryness and taken up in diisopropyl ether. The precipitate was filtered to yield 1.5 g of intermediate 20 (7.5%). The product was used without further purification in the next reaction step.

17.3.: [6-diethoxymethyl-5-ethyl-4-hydroxy-2-oxo-3-pyridinyl]-3,5-dimethylphenyl)-iodonium, hydroxide, inner salt (intermediate 21)

A mixture of intermediate 20 (3.4 g; 14 mmol) and Na₂CO₃ (3 g; 28 mmol) in water (50 ml) was stirred at room temperature for 15 min to give residue 1. A mixture of intermediate 2 (4.66 g; 15.4 mmol) and Na₂CO₃ (3 g; 28 mmol) in water (50 ml) was stirred at room temperature for 15 min to give residue 2. Residue 1 and residue 2 were combined and then stirred at room temperature for 2 hours. The precipitate was filtered off, washed with water and dried. Yield 8 g of intermediate 21; m.p.=125° C.).

17.4.: 6-(diethoxymethyl)-4-(3,5-dimethylphenoxy)-5-ethyl-3-iodo-2(1H)-pyridinone (compound 134)

A mixture of intermediate 21 (6 g; 12.7 mmol) in DMF (20 ml) was stirred at 120° C. for 1 hour. The solvent was evaporated till dryness to yield 5 g of compound 134 (83%). The residue was used immediately without further purification.

EXAMPLE 18 4-(3,5-dimethylphenoxy)-3-ethyl-1,6-dihydro-5-iodo-6-oxo-2-pyridinecarboxaldehyde (compound 159)

A mixture of compound 134 (5 g; 10 mmol) in HCl 3N (30 ml) and tetrahydrofurane (5 ml) was stirred at 100° C. for 30 min. and then extracted with CH₂Cl₂. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue (5 g) was crystallized from diisopropyl ether. The precipitate was filtered off and dried to yield 3.5 g of titled compound 159 (83%), m.p.=158° C.

The residue was used without further purification.

EXAMPLE 19 4-(3,5-dimethylphenoxy)-5-ethyl-6-(hydroxymethyl)-3-iodo-2(1H)-pyridinone (compound 133)

NaBH₄ (0.047 g; 1.3 mmol) was added to a mixture of compound 159 (0.5 g; 0.013 mol) in methanol (3 ml). The mixture was stirred at room temperature for 1 hour. Water was added. The precipitate was filtered off, taken up in diisopropyl ether and dried to yield 0.26 g (52%), m.p.=70° C.).

EXAMPLE 20 [3-(5-ethyl-3-iodo-6-methyl-2-oxo-1,2-dihydro-pyridin-4-yloxy)-5-iodo-phenyl]-acetonitrile (compound n° 426)

A mixture of compound 81 (0.1 g; 0.001 mol) and potassium cyanide (0.024 g; 0.0003 mol) in ethanol (2 ml) was stirred at 80° C. in a celled tube overnight. H₂O was added. The mixture was extracted with CH₂Cl₂. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 99/1; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.03 g) was crystallized from DIPE. The precipitate was filtered off and dried to yield 0.21 g (21%), m.p.=220° C.

EXAMPLE 21 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-[2-methylthiazol-4-ylmethylsulfanylmethyl)-1H-pyridin-2-one (compound n° 483)

21.1: 4-(3,5-dimethylphenoxy)-3-iodo-5-mercaptomethyl-6-methyl-1H-pyridin-2-one (compound n° 451)

A mixture of compound 125 (1.5 g; 0.0037 mol) and thiourea (0.31 g; 0.00408 mol) in DMSO (30 ml) was stirred at room temperature for 1 hour. NaOH 3N was added. The mixture was stirred for 15 minutes, acidified with HCl 3N and extracted with ethylacetate (EtOAc). The organic layer was separated, dried on magnesium sulfate (MgSO₄), filtered and the solvent was evaporated. The residue was taken up in DIPE and filtered. The precipitate (1.2 g) was purified by column chromatography over silica gel (eluent: EtOAc 100%; 35–70 μm) and dried to yield 0.3 g (20%).

21.2: 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-[2-methylthiazol-4-ylmethyl-sulfanylmethyl)-1H-pyridin-2-one (compound n° 483)

A mixture of compound 451 (0.07 g; 0.0001 mol) and 4-chloromethyl-2-methylthiazole (0.16 g, 0.0008 mol) in ethanol (3 ml) and triethylamine (0.2 ml) was stirred at 80° C. for 1 hour. H₂O was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated. The residue (0.04 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2; 15–40 μm). The pure fractions were collected and the solvent was evaporated and dried to yield 0.018 g.

EXAMPLE 22 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (compound 547)

22.1: 2-(1-amino-ethylidene)-5-phenyl-pentanoic acid ethyl ester (intermediate 23)

Ammonium nitrate (3.1 g; 0.039 mol) was added to a solution of intermediate 22 (2-acethyl-5-phenyl-pentanoic acid ethyl ester) (8.8 0.0354 mol) in tetrahydrofuran (90 ml). Ammoniac was bubbled. The mixture was stirred and refluxed for 6 hours, then stirred at room temperature for 12 hours, poured out into H₂O and extracted with CH₂Cl₂. The organic layer was separated, dried on magnesium sulfate (MgSO₄), filtered and the solvent was evaporated and dried to yield 8.3 g.

22.2: ethyl 4-hydroxy-6-methyl-2-oxo-5-(3-phenyl-propyl)-1,2dihydro-pyridine-3-carboxylic acid ethyl ester (intermediate 24)

Sodium ethoxide in ethanol (27.5 ml; 0.0738 mol) was stirred and refluxed. Malonic acid diethyl ester (11.8 ml; 0.0738 mol) was added dropwise. A solution of intermediate 23 (8.3 g; 0.0335 mol) in ethanol (30 ml) was added dropwise. The mixture was stirred and refluxed for 15 hours. Three-quarters of EtOH were evaporated. The mixture was poured out in ice, acidified with HCl 3N and extracted with EtOAc. The organic layer was separated, dried (MgSO₄), filtered and the solvent was evaporated The residue (19.5 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/NH₄OH 96/4/0.1; 15–35 μm). Two fractions were collected and the solvent was evaporated and dried to yield 0.43 g (4%).

22.3: 4-hydroxy-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (intermediate 25)

A mixture of intermediate 24 (0.1 g; 0.003 mol) and sodium hydroxide (0.038 g; 0.0009 mol) in H₂O (1.5 ml) was stirred and refluxed for 15 hours, then cooled to 5° C. with HCl 3N. The precipitate was filtered, washed with H₂O, then with isopropanol and dried to yield 0.07 g (91%).

22.4: 4-(3,5-dimethylphenoxy)-3-iodo-6-methyl-5-(3-phenyl-propyl)-1H-pyridin-2-one (compound 547)

A mixture of dichloro-3,5-dimethyliodobenzene (0.096 g; 0.0003 mol) and sodium carbonate (0.12 g; 0.0005 mol) in dimethylformamide (1 ml; 0.5 ml) was stirred at room temperature for 30 minutes. A solution of intermediate 25 (0.07 g; 0.0002 mol) and sodium carbonate (0.6 g; 0.0005 mol) in H₂O (0.5 ml) was added. The mixture was stirred at room temperature for 1 hour. The precipitate was filtered, washed with H₂O, then with DIPE and dried. The residue (0.12 g) was taken up in DMF and stirred at 100° C. for 30 minutes. The solvent was evaporated till dryness. The residue (0.1 g) was purified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH/NH₄OH 98/2/0 to 95/5/0.1; 35–70 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.07 g) was taken up in iPrOH. The precipitate was filtered off and dried to yield 0.06 g (44%), m.p.=220° C.

EXAMPLE 23 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-acrylonitrilephenoxy]pyridin-2(1H)-one (compound 470)

23.1. 3-Bromo-5-iodobenzaldehyde dichloride (intermediate 26)

3-Bromo-5-iodobenzaldehyde dichloride (intermediate 26) was obtained as described by H. J. Lucas and E. R. Kennedy, Org. Synth. (1955), III, 482–483.

23.2. 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-formylphenoxy]pyridin-2(1H)-one (compound 469)

Intermediate 26 (311 mg, 1 mmol) was suspended in 10 ml of water containing sodium carbonate (106 mg, 1 mmol) and stirred for 30 min. at room temperature. To this mixture a solution of 5-ethyl-6-methyl-4-hydroxypyridin-2(1H)-one (153 mg, 1 mmol) in 10 ml of water containing also Na₂CO₃ (106 mg, 1 mmol) was added. After stirring for 1 h at 20° C. the precipitate was filtered off, washed with water, dried in vacuo and suspended in dimethylformamide (5 mL). After heating at 120° C. for 10 min., the solvent was removed. Purification by flash chromatography (SiO₂, CH₂Cl₂/EtOH 98:2) gave the titled compound (205 mg, 44%) as yellow microcrystals, m.p.>260° C.

23.3. 6-methyl-5-ethyl-3-iodo-4-[(3-bromo,5-acrylonitrilephenoxy]pyridin-2(1H)-one (compound 470)

To a 0° C. magnetically stirred solution of diethyl(cyanomethyl)-phosphonate (113 μL, 0.68 mmol) in anhydrous THF (3 mL), NaH (28 mg; 0.68 mmol) was added (60% in mineral water). After stirring at room temperature for 1 h, compound 469 (80 mg; 0.17 mmol) was added and the reaction mixture was stirred 18 h at room temperature and poured into water (5 ml). The resulting solution was extracted with AcOEt, dried over MgSO₄ and evaporated. The oily residue obtained was then crystallized from Et₂O to give the pure titled compound (65 mg; 77%), m.p.>260° C.

Table 1 lists intermediates and compounds of formula (I) which were made analogous to one of the above examples.

N° = Y Q X—R1 R2 R3 R4 mp. ° C./[MH+] 1 O I

Me H 245 Chemistry 5 Chemistry 6 2 O I

Me H >250  Chemistry 11 Chemistry 12 3 O I

Me H >250  Chemistry 17 Chemistry 18 4 O I

Et

H 210 Chemistry 23 Chem 25 5 O I

Me H >250  Chemistry 29 Chemistry 30 6 O I

Me H [520] Chemistry 35 Chemistry 36 7 O I—Pr

Et Me H 260–262 Chemistry 41 8 O I

Me H 230 Chemistry 47 Chemistry 48 9 O I

H 125 Chemistry 53 Et Chem 55 10 O I

Me H [639] Chemistry 59 Chemistry 60 11 O I

Me H [569] Chemistry 65 Chemistry 66 12 O I

Me H [593] Chemistry 71 Chemistry 72 13 O I

Me H [539] Chemistry 77 Chemistry 78 14 O I

Me H [543] Chemistry 83 Chemistry 84 15 O I

Me H [551] Chemistry 89 Chemistry 90 16 O I

Me H [539] Chemistry 95 Chemistry 96 17 O I

Me H [531] Chemistry 101 Chemistry 102 18 O I

Me H [477] Chemistry 107 Chemistry 108 19 O I

Me H [463] Chemistry 113 Chemistry 114 20 O I

Me H [531] Chemistry 119 Chemistry 120 21 O

I Me H 240–244 Chem 124 Chemistry 125 22 O

H Me H 192–194 Chem 130 Chemistry 131 23 O I

Et Me H 102–104 Chemistry 137 24 O I

Et Me H 170–172 Chemistry 143 25 O I

Et Me H 225–226 Chemistry 149 26 O I

Et Me H 236–238 Chemistry 155 27 O I

Et Me H 260–262 Chemistry 161 28 O I

Et

H 118 Chemistry 167 Chem 169 29 O I

Et

H 184 Chemistry 173 Chem 175 30 O I

Me H 160 Chemistry 179 Chemistry 180 31 O I

Me H 165 Chemistry 185 Chemistry 186 32 O I

Me H >250  Chemistry 191 C═NOH 33 O I

Me H 150 Chemistry 197 Chemistry 198 34 O I

Me H >250  Chemistry 203 Chemistry 204 35 O I

Me H >250  Chemistry 209 Chemistry 210 36 O I

Me H 200 Chemistry 215 Chemistry 216 37 O I

Et

H [519] Chemistry 221 Chem 223 38 O I

Et

H — Chemistry 227 Chem 229 39 O I

Me H 210 Chemistry 233 Chemistry 234 40 O I

Et

H 210 Chemistry 239 Chem 241 41 O I

Et

H >250 Chemistry 245 C═NOH 42 O I

Me H >250 Chemistry 251 Chemistry 252 43 O I

Me H 230 Chemistry 257 Chemistry 258 44 O I

Me H 120 Chemistry 263 Chemistry 264 45 O I

Me H 210 Chemistry 269 Chemistry 270 46 O I

Me H 250 Chemistry 275 Chemistry 276 47 O I

Me H >250  Chemistry 281 Chemistry 282 48 O I

Et

H 218 Chemistry 287 Chem 289 49 O I

Me H >250  Chemistry 293 Chemistry 294 50 O I

Et

H 226 Chemistry 299 Chem 301 51 O I

Me H 236 Chemistry 305 Chemistry 306 52 O I

Me H >250  Chemistry 311 Chemistry 312 53 O I

Me H >250  Chemistry 317 Chemistry 318 54 O I

Me H 150 Chemistry 323 Chemistry 324 55 O I

Me H >250  Chemistry 329 CN 56 O H

Me H >250  Chemistry 335 CN 57 O I

Me H >250  Chemistry 341 Formyl 58 O I

Et

H 182 Chemistry 347 Chem 349 59 O I

Me H 245 Chemistry 353 CH2NMe2 60 O I

Me H 218 Chemistry 359 CH2Cl 61 O I

Me H 240 Chemistry 365 CH2OH 62 O I

Et

H 165 Chemistry 371 Chem 373 63 O I

Et

H 235 Chemistry 377 Chem 379 64 O I

Me H >250  Chemistry 383 Chemistry 384 65 O I

Me H >250  Chemistry 389 CO2H 66 O I

Et

H 240 Chemistry 395 CH2CN 67 O I

Et

H [502] Chemistry 401 Chem 403 68 O Me

Et Me H 207–209 Chemistry 407 69 O H

Et Me H — Chemistry 413 70 O I

Et

H 224 Chemistry 419 Chem 421 71 O I

Me H 210 Chemistry 425 CO2Et 72 O H

Me H 230 Chemistry 431 CO2Et 73 O I

Et

H 181 Chemistry 437 Chem 439 74 O I

Et

H 170 Chemistry 443 Chem 445 75 O I

Et

H  95 Chemistry 449 Chem 451 76 O I

Me H 112 Chemistry 455 Chemistry 456 77 O H

CO2Et

H 216–218 Chemistry 461 Azido 78 O I

Ph H H 230–232 Chemistry 467 79 O I

Et Me H 138–139 Chemistry 473 80 O I

Et Me H 178–149 Chemistry 479 81 O I

Et Me H 248–250 Chemistry 485 82 O I

Et Me H 202–204 Chemistry 491 83 O I

Et Me H 258–260 Chemistry 497 84 O H

Me H 205–207 Chemistry 503 Chemistry 504 85 O Br

Me H 183–184 Chemistry 509 Chemistry 510 86 O I

Me H 220–222 Chemistry 515 Chemistry 516 87 O CO2Et

Et Me H 189–191 Chemistry 521 88 O I

Et Me H — Chemistry 527 89 O H

Et Me H 229–231 Chemistry 533 90 O I

Et Me H 288–290 Chemistry 539 91 O I

Me H 238 Chemistry 545 CH2NMe2 92 O I

Me H 220 Chemistry 551 Chemistry 552 93 O I

Et

H 160 Chemistry 557 Chem 559 94 O I

Me H 218 Chemistry 563 Chemistry 564 95 O I

Et

H 214 Chemistry 569 Chem 571 96 O I

Et

H 190 Chemistry 575 Chem 577 97 O I

Me H >250   Chemistry 581 Chemistry 582 98 O I

Et

H 240 Chemistry 587 Chem 589 99 O I

Me H 180 Chemistry 593 Chemistry 594 100 O I

Me H >250  Chemistry 599 Ac 101 O I

Et

210 Chemistry 605 (CH2)3 102 O I

Et

H 170 Chemistry 611 Chem 613 103 O I

Et

H 170 Chemistry 617 Chem 619 104 O I

Et

H 200 Chemistry 623 Chem 625 105 O I

Et

H >250  Chemistry 629 Chemistry 631 106 O I

CO2Et

H 216–218 Chemistry 635 Azido 107 O I

Et Me H 263–265 Chemistry 641 108 O I

Et Me H — Chemistry 647 109 O Br

Et Me H 187–189 Chemistry 653 110 O I

Me H 240 Chemistry 659 Chemistry 660 111 O CO2Et

Et Me H 202–204 Chemistry 665 112 O H

CN NH2 H 282–283 Chemistry 671 113 O I

CN NH2 H 283–285 Chemistry 677 114 O H

Et Me H 166–168 3-Methylbenzyl 115 O I

Et Me H 229–231 Chemistry 695 116 O Br

Et CH2Br H [430] Chemistry 701 117 O H

Et Me H — Chemistry 707 118 O I

Et Me H — Chemistry 713 119 O I

Et Me H 266–267 Chemistry 719 120 O I

Et Me H 186–187 Chemistry 725 121 O I

Et Me H 225–226 Chemistry 731 122 O I

CN

H 225–227 Chemistry 737 Azido 123 O I

Me H [539] Chemistry 743 Chemistry 744 124 O I

Me H 140 Chemistry 749 Chemistry 750 125 O I

CH2Cl Me H 256–258 Chemistry 755 126 O I

Me H >250  Chemistry 761 Chemistry 762 127 O I

Me H — Chemistry 767 C═C(CN)2 128 O I

Me H >240  Chemistry 773 Chemistry 774 129 O I

Me H 230 Chemistry 779 Chemistry 780 130 O I

Et

H 180 Chemistry 785 Chem 787 131 O I

Et

H 130 Chemistry 791 CH2NMe2 132 O I

Et CH2Cl H >240  Chemistry 797 133 O I

Et CH2OH H  97 Chemistry 803 134 O I

Et

H — Chemistry 809 Chem 811 135 O I

Me H >250  Chemistry 815 Chemistry 816 136 O I

Me H >250  Chemistry 821 Chemistry 822 137 O I

Me H >250  Chemistry 827 Chemistry 828 138 O I

Me H 250 Chemistry 833 Chemistry 834 139 O I

Et

H [442] Chemistry 839 Chem 841 140 O I

Me H >250 Chemistry 845 CH═CHCN 141 O I

Me H [508] Chemistry 851 Chemistry 852 142 O I

Me H [491] Chemistry 857 Chemistry 858 143 O I

Me H [529] Chemistry 863 Chemistry 864 144 O I

Me H [540] Chemistry 869 Chemistry 870 145 O I

Me H [545] Chemistry 875 Chemistry 876 146 O I

Me H [543] Chemistry 881 Chemistry 882 147 O I

Me H [593] Chemistry 887 Chemistry 888 148 O I

Me H [544] Chemistry 893 Chemistry 894 149 O I

Me H [570] Chemistry 899 Chemistry 900 150 O I

Me H [516] Chemistry 905 Chemistry 906 151 O I

Me H [519] Chemistry 911 Chemistry 912 152 O I

Me H [569] Chemistry 917 Chemistry 918 153 O I

Me H [535] Chemistry 923 Chemistry 924 154 O I

Me H [572] Chemistry 929 Chemistry 930 155 O I

Me H [586] Chemistry 935 Chemistry 936 156 O I

Me H [518] Chemistry 941 Chemistry 942 157 O I

Et

H 195 Chemistry 947 Chem 949 158 O I

Et

H 200 Chemistry 953 Chem 955 159 O I

Et

H 158 Chemistry 959 Formyl 160 O I

Me H >250  Chemistry 965 Chemistry 966 161 O I

Me H 195 Chemistry 971 Chemistry 972 162 O I

Me H 220 Chemistry 977 Chemistry 978 163 O I

Me H >240  Chemistry 983 C═CHAc 164 O I

Me H >240  Chemistry 989 Chemistry 990 165 O I

Me H >240  Chemistry 995 Chemistry 996 166 O I

Me H >250  Chemistry 1001 Chemistry 1002 167 O I

Me H 242 Chemistry 1007 Chemistry 1008 168 O I

Me H 262 Chemistry 1013 Chemistry 1014 169 O I

Me H >250  Chemistry 1019 Chemistry 1020 170 O I

Me H 230 Chemistry 1025 Chemistry 1026 171 O I

Me H [573] Chemistry 1031 Chemistry 1032 172 O I

Me H [561] Chemistry 1037 Chemistry 1038 173 O I

Me H [593] Chemistry 1043 Chemistry 1044 174 O I

Me H [526] Chemistry 1049 Chemistry 1050 175 O I

Me H [441] Chemistry 1055 Chemistry 1056 176 O I

Me H >250  Chemistry 1061 C═NOH 177 O H

Et Me H — Chemistry 1067 178 O CO2Et

Et Me H — Chemistry 1073 179 O CO2Et

Et Me H — Chemistry 1079 180 O n-Pr

Et Me H 158–160 Chemistry 1085 181 O I

Me H H >260  Chemistry 1091 182 O

Et Me H 158–160 Chem 1096 Chemistry 1097 183 O

Et Me H 159–161 Chem 1102 Chemistry 1103 184 O I

CN

H 261–262 Chemistry 1109 Chem 1111 185 O I

CN

H 263–264 Chemistry 1115 Chem 1117 186 O I

CN

H 265–267 Chemistry 1121 SPh 187 O I

CN

H 224–225 Chemistry 1127 Chem 1129 188 O I

CN

H 218–220 Chemistry 1133 Chem 1135 189 O I

CN

H 235–237 Chemistry 1139 Chem 1141 190 O I

CN

H 242–244 Chemistry 1145 Chem 1147 191 O I

Et CH2CH2Ph H 240 Chemistry 1151

192 O I

Me H [514] Chemistry 1157 Chemistry 1158 193 O I

Me H [529] Chemistry 1163 Chemistry 1164 194 O I

Me H [580] Chemistry 1169 Chemistry 1170 195 O I

H [504] Chemistry 1175 Chemistry 1176 Me 196 O I

Me H [562] Chemistry 1181 Chemistry 1182 197 O I

Me H [518] Chemistry 1187 Chemistry 1188 198 O I

Me H [456] Chemistry 1193 Chemistry 1194 199 O I

Me H [503] Chemistry 1199 Chemistry 1200 200 O I

Me H [545] Chemistry 1205 Chemistry 1206 201 O I

Me H [469] Chemistry 1211 Chemistry 1212 202 O I

Me H [513] Chemistry 1217 Chemistry 1218 203 O I

Me H [538] Chemistry 1223 Chemistry 1224 204 O I

Me H [481] Chemistry 1229 Chemistry 1230 205 O I

Me H [490] Chemistry 1235 Chemistry 1236 206 O I

Me H [492] Chemistry 1241 Chemistry 1242 207 O I

Me H [542] Chemistry 1247 Chemistry 1248 208 O I

Me H [505] Chemistry 1253 Chemistry 1254 209 O I

Me H [487] Chemistry 1259 Chemistry 1260 210 O I

Me H [452] Chemistry 1265 Chemistry 1266 211 O I

Me H [516] Chemistry 1271 Chemistry 1272 212 O I

Me H [514] Chemistry 1277 Chemistry 1278 213 O I

Me H [427] Chemistry 1283 Chemistry 1284 214 O I

Me H >250 Chemistry 1289 Chemistry 1290 215 O I

Me H >250 Chemistry 1295 CH═CHCO2Et 216 O I

Et

H 160 Chemistry 1301 Chem 1303 217 O I

Et

H 230 Chemistry 1307 Chem 1309 218 O I

Me H >250 Chemistry 1313 Chemistry 1314 219 O I

Me H >250 Chemistry 1319 Chemistry 1320 220 O I

CH2NH2 Me H 240 Chemistry 1325 221 O I

H 264–266 Chemistry 1331 Chemistry 1332 222 O I

H 252–253 Chemistry 1337 (CH2)4 223 O I

H 243–244 Chemistry 1343 (CH2)3 224 O H

H 260–262 Chemistry 1349 Chemistry 1350 225 O I

CO2Et Me H 190 Chemistry 1355 226 O I

Et Cl NH2 146–147 Chemistry 1361 227 O I

CN

H 282–284 Chemistry 1367 Chem 1369 228 O I

CO2Et Cl H 180–182 Chemistry 1373 229 O H

CN Cl H 240–242 Chemistry 1379 230 O

Et Me H 188–190 Chem 1384 Chemistry 1385 231 O Et

Et Me H 179–181 Chemistry 1391 232 O I

Me H >240 Chemistry 1397 Chemistry 1398 233 O I

Me H [539] Chemistry 1403 Chemistry 1404 234 O Vinyl

Et Me H 198–200 Chemistry 1409 235 O H

H — Chemistry 1415 (CH2)3 236 O I

CN Cl H 276–277 Chemistry 1421 237 O I

Et Me H 280–282 Chemistry 1427 238 O I

CN Me H >240 Chemistry 1433 239 O I

Me H >240 Chemistry 1439 Chemistry 1440 240 O I

Me H — Chemistry 1445 Chemistry 1446 241 O I

Me H >240 Chemistry 1451 Chemistry 1452 242 O I

Me H 220 Chemistry 1457 Chemistry 1458 243 O I

Me H 216–217 Chemistry 1463 Chemistry 1464 244 O I

Me H 216–218 Chemistry 1469 Chemistry 1470 245 O I

Me H 212–214 Chemistry 1475 Chemistry 1476 246 O

Et Me H — Chem 1480 3-Methylbenzyl 247 S H

Et Me H >240 Chemistry 1487 248 S I

Et Me H 210 Chemistry 1493 249 O I

2-Methoxybenzyl Me H 156 Chemistry 1505 250 O I

Me H 141 Chemistry 1511 Chemistry 1512 251 O

Et Me H — Chem 1516 3-Methylbenzyl 252 O

Et Me H — Chem 1522 3-Methylbenzyl 253 O I

Me H 184–186 Chemistry 1529 Chemistry 1530 254 O I

Me H 224–226 Chemistry 1535 Chemistry 1536 255 O I

Me H 234–236 Chemistry 1541 Chemistry 1542 256 O I

H H 160–162 Chemistry 1547 Chemistry 1548 257 O I

CH2OH Me H 248–250 Chemistry 1553 258 O I

Et Me Me 240 Chemistry 1559 259 O I

Et Me

179 Chemistry 1565 Chem 1562 260 O SOMe

Et Me H 196–197 Chemistry 1571 261 O I

Et Cl H 186–187 Chemistry 1577 262 O H

Me Cl H 210–242 Chemistry 1583 263 O I

Me Cl H 240–242 Chemistry 1589 264 O I

2-Methoxyethyl Me H 212 Chemistry 1595 265 O H

Me

H 176 3-Methylbenzoyl Chem 1603 266 O I

Me

H >260 3-Methylbenzoyl Chem 1609 267 O H

Et Cl H 210–211 Chemistry 1613 268 O CH2OH

H Me H 212–214 Chemistry 1619 269 O I

Me H 282–284 Chemistry 1625 Formyl 270 O

Et Me H 192 Chem 1630 Chemistry 1631 271 O

Et Me H 182 Chem 1636 Chemistry 1637 272 O SMe

Et Me H 186–188 Chemistry 1643 273 O

Et Me H [336] Chem 1648 3-Methylbenzyl 274 S

Et Me H [313] Chem 1654 3-Methylbenzyl 275 O CO2Me

Et Me H [300] 3-Methylbenzyl 276 O C═NOH

Et Me H 262 Chemistry 1667 277 O OMe

Et Me H 178 Chemistry 1673 278 O

Et Me H 225 Chem 1678 Chemistry 1679 279 O

Et Me H 166 Chem 1684 Chemistry 1685 280 O SPh

Et Me H 211 Chemistry 1691 281 O CH(OH)Ph

Et Me H 198 Chemistry 1697 282 O CO2Et

Et Me H — 3-Methylbenzyl 283 O CO2H

Et Me H — 3-Methylbenzyl 284 O Br

Et Me H 240–241 Chemistry 1715 285 O CN

Et Me H 282–284 Chemistry 1721 286 O I

Et Me H 204–206 3-Methylbenzyl 287 O I

H Me H 274–275 Chemistry 1733 288 O CCPh

Et Me H 260 Chemistry 1739 289 O CH═CHCO2Et

Et Me H 256 Chemistry 1745 290 O Formyl

Et Me H 228 Chemistry 1751 291 O 3-Thiophenyl

Et Me H 222 Chemistry 1757

292 O 3-Cl-phenyl

Et Me H 223 Chemistry 1763 293 O 2-Furyl

Et Me H 228 Chemistry 1769 294 O CH2OH

Et Me H 200 Chemistry 1775 295 O CO2H

Et Me H 221 Chemistry 1781 296 O I

Et Me H 232–234 Chemistry 1787 297 O I

Et Me H 248–250 Chemistry 1793 298 O I

Et Me H 250 Chemistry 1799 299 O I

Et Me H 265–266 Chemistry 1805 300 O I

Et Me H 275–276 Chemistry 1811 301 O CO2H

H H H [290] 2,5-Dimethoxybenzyl 302 O H

H Me H [283] Chemistry 1823 303 O CO2Et

H Me H [355] Chemistry 1829 304 O CO2H

H Me H [299] Chemistry 1835 305 O CO2Et

H Me H [303] Chemistry 1841 306 O I

Et Me H 200–202 Chemistry 1859 307 O I

Et Me H 238–240 Chemistry 1865 308 O H

Et Me H 212–214 3,5-Dimethylbenzyl 309 O I

Et Me H 258–260 Chemistry 1877 310 O I

Et Me H — Chemistry 1883 311 O I

Et Me H 198–199 Chemistry 1889 312 O I

Et Me H 182–183 Chemistry 1895 313 O I

Et Me H 265–266 Chemistry 1901 314 O I

Et H H 210–212 Chemistry 1907 315 O I

Me Me H 261–262 Chemistry 1913 316 O I

H 218–219 Chemistry 1919 Chemistry 1920 317 O I

H 230–232 Chemistry 1925 (CH2)4 318 O I

H 206–208 Chemistry 1931 (CH2)3 319 O I

Et Me H 242–243 Chemistry 1937 320 O H

Et Me H 241–242 Chemistry 1943 321 O I

Et Me H 198–200 Chemistry 1949 322 O I

Et Me H — Chemistry 1955 323 O CO2Et

Et Me H 198 Chemistry 1961 324 O CO2Et

Et Me H 184–185 3,5-Dimethylbenzyl 325 O H

Et Me H 232–233 Chemistry 1973 326 O I

Et Me H 240 Chemistry 1979 327 O H OPh Et Me H 228–229 328 O I OPh Et Me H 180–182 329 O I OPh H Me H 265–266 330 O CO2Et

Et Me H 228–229 Chemistry 2003 331 O

Et Me H 192–193 Chem 2008 3,5-Dimethylbenzyl 332 O CO2H

Et Me H — 3,5-Dimethylbenzyl 333 O CN

H n-Pr H 132 Benzyl 334 O

Et Me H 207 Chem 2026 3-Methylbenzoyl 335 O

Et Me H 216 Chem 2032 3-Methylbenzyl 336 O CH2NMe2

H 185 3-Methylbenzyl (CH2)4 337 O CH2NH2

H — 3-Methylbenzyl (CH2)4

N^(o) = Q X-R1 R2 R3 R4 mp. ° C./(MH+) 338

H 245 I Chemistry 3 Chemistry 4 Me 339

H 175 I Chemistry 8 Chemistry 9 Me 340

H [460] I Chemistry 13 Chemistry 14 Me 341

H [324, 326] H Chemistry 18 Et Me 342

H [292, 294] Cl Chemistry 23 Et Me 343

H [288] Chemistry 27 Chemistry 28 344

H [462] I Chemistry 33 Et Me 345

H [588] I Chemistry 38 Et Me 346

H [506 I Chemistry 43 Chemistry 44 Me 347

H [304] CH2OH Chemistry 48 Et Me 348

H [627] I Chemistry 53 Et Me 349

H [610] I Chemistry 58 Et Me 350

H [616] I Chemistry 63 Et Me 351

H [604] I Chemistry 68 Et Me 352

H [615] I Chemistry 73 Et Me 353

H [579 I Chemistry 78 Et Me 354

H [596] I Chemistry 83 Et Me 355

H [640] I Chemistry 88 Et Me 358

H [614] I Chemistry 93 Et Me 357

H 205 I Chemistry 98 Chemistry 99 Me 358

H 210 I Chemistry 103 Chemistry 104 Me 359

H >250 I Chemistry 108 Chemistry 109 Me 360

H [487] I Chemistry 113 Chemistry 114 Me 381

H [570] I Chemistry 118 Chemistry 119 Me 362

H [455] I Chemistry 123 Chemistry 124 Me 363

H 215 I Chemistry 128 Chemistry 129 Me 364

H 205 I Chemistry 133 Chemistry 134 Me 365

H >250 I Chemistry 138 Chemistry 139 Me 366

H 240 I Chemistry 143 Chemistry 144 Me 367

H 135 I Chemistry 148 Chemistry 149 Me 368

H >250 I Chemistry 153 Chemistry 154 Me 369

H >250 I Chemistry 158 Chemistry 159 Me 370

H >250 I Chemistry 163 Chemistry 164 Me 371

H >250 I Chemistry 168 Chemistry 169 Me 372

H >250 I Chemistry 173 Chemistry 174 Me 373

H >250 I Chemistry 178 Chemistry 179 Me 374

H 170 I Chemistry 183 Chemistry 184 Me 375

H 220 I Chemistry 188 Chemistry 189 Me 376

H >250 I Chemistry 193 Chemistry 194 Me 377

H >250 I Chemistry 198 Et Chemistry 200 378

H >250 I Chemistry 203 Chemistry 204 Me 379

H [395] I Chemistry 208 Et CN 380

H [399] I Chemistry 213 Et CH2NH2 381

H 230 I Chemistry 218 Chemistry 219 Me 382

H 226 I Chemistry 223 Chemistry 224 Me 383

H [532] Chemistry 227 Chemistry 228 384

H [540] I Chemistry 233 Chemistry 234 Me 385

H [512] I Chemistry 238 Chemistry 239 Me 386

H [256] Vinyl Chemistry 243 H Me 387

H [258] Et Chemistry 248 H Me 388

H [384] Et Chemistry 253 I Me 389

H >250 I Chemistry 258 Chemistry 259 Me 390

H >250 I Chemistry 263 Chemistry 264 Me 391

H >250 I Chemistry 268 CH2NH2 Me 392

H 239 I Chemistry 273 Chemistry 274 Me 393

H 220 I Chemistry 278 Chemistry 279 Me 394

H [458] I Chemistry 283 Chemistry 284 Me 395

H 240 I Chemistry 288 Chemistry 289 Me 396

H 190 I Chemistry 293 Chemistry 294 Me 397

H >240 I Chemistry 298 Chemistry 299 Me 398

H >250 I Chemistry 303 Chemistry 304 Me 399

H >250 I Chemistry 308 Chemistry 309 Me 400

H >250 I Chemistry 313 Chemistry 314 Me 401

H 212 I Chemistry 318 Chemistry 319 Me 402

H 238 I Chemistry 323 Chemistry 324 Me 403

H 188 I Chemistry 328 Chemistry 329 Me

404

H 104 I Chemistry 333 Chemistry 334 Me 405

H 240 I Chemistry 338 Chemistry 339 Me 406

H 148 I Chemistry 343 Chemistry 344 Me 407

H 214 I Chemistry 348 Et Chemistry 350 408

H [308, 310] Cl Chemistry 353 Et Me 409

H [326] CF3 Chemistry 358 Et Me 410

H [541] I Chemistry 363 Chemistry 364 Me 411

H [429] I Chemistry 368 Chemistry 369 Me 412

H 220 I Chemistry 373 Chemistry 374 Me 413

H >250 I Chemistry 378 Chemistry 379 Me 414

H [557] I Chemistry 383 Chemistry 384 Me 416

H 162 I Chemistry 388 Chemistry 389 Me 416

H ><240 I Chemistry 393 Chemistry 394 Me 417

H [328] Chemistry 397 Chemistry 398 Et Me 418

H [362, 364] Chemistry 402 Chemistry 403 Et Me 419

H 248 I Chemistry 408 Chemistry 409 Me 420

H 226 I Chemistry 413 Chemistry 414 Me 421

H 174 I Chemistry 418 Chemistry 419 Me 422

H [350] H Chemistry 423 Et CH(OH)Ph 423

H [476] I Chemistry 428 Et CH(OH)Ph 424

H 158 I Chemistry 433 Chemistry 434 Me 425

H 236 I Chemistry 438 Chemistry 439 Me 426

H [521] I Chemistry 443 Et Me 427

H 234 I Chemistry 448 Chemistry 449 Me 428

H 204 I Chemistry 463 Chemistry 464 Me 429

H [556] I Chemistry 458 CO2Et Me 430

H [574] I Chemistry 463 Et Me 431

H [410] Chemistry 467 Chemistry 468 Et Me 432

H [432] Chemistry 472 Chemistry 473 Et Me 433

H 236 I Chemistry 478 Chemistry 479 Me 434

H >250 I Chemistry 483 Chemistry 484 Me 435

H 200 I Chemistry 488 Chemistry 489 Me 436

H >250 I Chemistry 493 Chemistry 494 Me 437

H [442] I Chemistry 488 Et Chemistry 500 438

H 186 I Chemistry 503 Et Chemistry 505 439

H [370] I Chemistry 508 Me Me 440

H [514] I Chemistry 513 CH2OH Me 441

H [372] I Chemistry 518 Me Me 442

H [390, 392] I Chemistry 523 Me Me 443

H [380] I Chemistry 528 Me Me 444

H [430] I Chemistry 533 Me Me 445

H [314] Chemistry 537 Chemistry 538 Et Me 446

H [356] Chemistry 542 Chemistry 543 Et Me 447

H [525] I Chemistry 548 Et Me 448

H [535] I Chemistry 553 Et Me 449

H >240 I Chemistry 558 Chemistry 559 Me 450

H 230 I Chemistry 563 Chemistry 564 Me 451

H 230 I Chemistry 566 Chemistry 569 Me 452

H 140 I Chemistry 573 Chemistry 574 Me 453

H 210 I Chemistry 578 CO2Me CH2OMe 454

H 230 I Chemistry 583 CH2OH CH2OMe 455

H [434, 436] I Chemistry 588 CH2Cl CH2OMe 456

H 232 I Chemistry 593 Chemistry 594 CH2OMe 457

H 230 I Chemistry 598 Chemistry 599 CH2OH 458

H 188 I Chemistry 603 Chemistry 604 Me 459

H 190 I Chemistry 608 Chemistry 609 Me 460

H 240 I Chemistry 613 Chemistry 614 Me 461

H 204 I Chemistry 618 Chemistry 619 Me 462

H 248 I Chemistry 623 Chemistry 624 Me 463

H 220 I Chemistry 628 Chemistry 629 Me 464

H [583] I Chemistry 633 Chemistry 634 Me 465

H [576, 578] I Chemistry 638 Chemistry 639 Me 466

H [560, 562] I Chemistry 643 Chemistry 644 Me 467

H [542] I Chemistry 648 Chemistry 649 Me 468

H [558] I Chemistry 653 Chemistry 654 Me 469

H [462, 464] I CHemistry 658 Et Me 470

H [485, 487] I Chemistry 663 Et Me 471

H [380] Chemistry 567 Chemistry 668 Et Me 472

H [506] I Chemistry 673 Et Me 473

H [507] I Chemistry 678 Et Me 474

H 165 H Chemistry 683 CO2Me CH2OMe 475

H [306] H Chemistry 688 CH2OH CH2OMe 476

H 142 I Chemistry 683 CO2Me CH2OMe 477

H 198 I Chemistry 698 CH2OH CH2OMe 478

H I Chemistry 703 CH2Cl CH2OMe 479

H 115 I Chemistry 708 Chemistry 709 CH2OMe 480

H [487] I Chemistry 713 Chemistry 714 CH2OH 481

H 230 I Chemistry 718 Chemistry 719 Me 482

H 168 I Chemistry 723 Chemistry 724 Me 483

H [513] I Chemistry 728 Chemistry 729 Me 484

H 200 I Chemistry 733 Chemistry 734 Me 485

H [486] I Chemistry 738 Chemistry 739 Me 486

H 220 I Chemistry 743 Chemistry 744 Me 487

H 174 I Chemistry 748 Chemistry 749 Me 488

H 204 I Chemistry 753 Chemistry 754 Me 489

H >250 I Chemistry 758 Chemistry 759 Me 490

H 162 I Chemistry 763 Chemistry 764 Me 491

H [600] I Chemistry 768 Chemistry 769 Me 492

H [500] I Chemistry 773 Chemistry 774 Me 493

H 164 I Chemistry 778 Chemistry 779 Me 494

H [513] I Chemistry 783 Chemistry 784 Me 495

H 206 I Chemistry 788 Chemistry 789 Me 496

H 185 I Chemistry 793 Chemistry 794 Me 497

H [460] I Chemitsyr 798 Chemistry 799 CH2OMe 498

H [498] I Chemistry 803 Chemistry 804 Me 499

H [495] I Chemistry 808 Chemistry 809 Me 500

H 203 I Chemistry 813 Chemistry 814 Me 501

H 204 I Chemistry 818 Chemistry 819 Me 502

H 168 I Chemistry 823 Chemistry 824 Me 503

H 217 I Chemistry 828 Chemistry 829 Me 504

H 200 I Chemistry 833 Chemistry 834 Me 505

H Me Chemistry 838 CH2Cl Me 506

H 206 Me Chemistry 843 Chemistry 844 Me 507

H 170 Me Chemistry 848 CO2Et Me 508

H 218 Me Chemistry 853 CH2OH Me 509

H 200 Me Chemistry 858 Chemistry 859 Me 510

H 166 I Chemistry 863 Chemistry 864 Me 511

H 213 I Chemistry 868 Chemistry 869 512

H [610] I Chemistry 873 Chemistry 874 Me 513

H [751] I Chemistry 878 CO2Et Me 514

H [567] I Chemistry 883 Chemistry 884 Me 515

H [418, 420] I Chemistry 888 Et Me 516

H [472] I Chemistry 893 Et Me 517

H [621] I Chemistry 898 Chemistry 899 Me 518

H [416] I Chemistry 903 Et Me 519

H [556] I Chemistry 908 Chemistry 909 Me 520

H [452, 454, 456] I Chemistry 913 Et Me 521

H [434, 436] I Chemistry 918 Et Me 522

H [476] I Chemistry 923 Et Me 523

H [517] I Chemistry 928 Chemistry 929 Me 524

H [362] Chemistry 932 Chemistry 933 Et Me 525

H [361] Chemistry 937 Chemistry 938 Et Me 526

H [450] I Chemistry 943 Chemistry 944 Me 527

H [399] I Chemistry 948 Et Me 528

H [381] I Chemistry 953 Et Me 529

H [282] I Chemistry 958 Chemistry 959 Me 530

H 210 I Chemistry 963 Chemistry 964 Me 531

H 144 I Chemistry 968 Chemistry 969 Me 532

H [512] I Chemistry 973 CH2OH Me 533

H [579 I Chemistry 978 Chemistry 979 Me 534

H [469] I Chemistry 983 Chemistry 984 Me 535

H [485] I Chemistry 988 Chemistry 989 Me 536

H [380] I Chemistry 993 Et Me 537

H [424] I Chemistry 998 Et Me 538

H [494] I Chemistry 1003 Chemistry 1004 Me 539

H 203 I Chemistry 1008 Chemistry 1009 Me 540

H 230 I Chemistry 1013 Chemistry 1014 Me 541

H [510] I Chemistry 1018 Chemistry 1019 Me 542

H 206 Me Chemistry 1023 Chemistry 1024 Me 543

H >250 Me Chemistry 1028 Chemistry 1029 Me 544

H [560, 562, 564] I Chemistry 1033 Chemistry 1034 Me 545

H 248 I Chemistry 1038 Chemistry 1039 Me 546

H 100 I Chemistry 1043 Chemistry 1044 Me 547

H 220 I Chemistry 1048 Chemistry 1049 Me 548

H [459] I Chemistry 1053 Et Me 549

H [431] I Chemistry 1058 Et Me 550

H [398] I Chemistry 1063 Et Me 551

H [421] I Chemistry 1068 Et Me 552

H [370] I Chemistry 1073 Et Me 553

H [298] H Chemistry 1078 Et Me 554

H [424] I Chemistry 1083 Et Me 555

H [376, 378] Br Chemistry 1088 Et Me 556

H [600] I Chemistry 1093 Et Me 557

H [435] I Chemistry 1098 Et Me 558

H 194 I Chemistry 1103 Chemistry 1104 Me 559

H 146 I Chemistry 1108 Chemistry 1109 Me 560

H 168 I Chemistry 1113 Chemistry 1114 Me 561

H >250 I Chemistry 1118 Chemistry 1119 Me 562

H I Chemistry 1123 Chemistry 1124 Me 563

H 232 I Chemistry 1128 Chemistry 1129 Me 564

H >250 I Chemistry 1133 Chemistry 1134 Me 565

H 235 H Chemistry 1138 CO2Et Chemistry 1140 566

H 210 I Chemistry 1143 Chemistry 1144 Me 567

H 202 Vinyl Chemistry 1148 Chemistry 1149 Me 568

H [330] H Chemistry 1153 Chemistry 1154 Me 569

H [302] H Chemistry 1158 CH2CH2CO2H Me 570

H [371] H Chemistry 1163 Chemistry 1164 Me 571

H >250 I Chemistry 1168 Chemistry 1169 Me 572

H 230 I Chemistry 1173 Chemistry 1174 Me 573

H 249 I Chemistry 1178 Chemistry 1179 Me 574

H >250 I Chemistry 1183 Chemistry 1184 Me 575

H 216 I Chemistry 1188 Chemistry 1189 Me 576

H >250 I Chemistry 1193 Chemistry 1194 Me 577

H [472] I Chemistry 1198 Et Me 578 I

Me H [427] Chemistry 3 Et 579 I

Me H [468] Chemistry 8 Et 580 I

Me H [467] Chemistry 13 Et 581 I

Me H [469] Chemistry 18 Et 582 I

Me H [502] Chemistry 23 Et 583 I

Me H [515] Chemistry 28 Et 584 I

Me H [498] Chemistry 33 Et 585 I

Me H 180 Chemistry 38 Chemistry 39 586 I

Me H 168 Chemistry 43 Chemistry 44 587 I

Me H 236 Chemistry 48 Chemistry 49 588 I

Me H 228 Chemistry 53 Chemistry 54 589 I

Me H >250 Chemistry 58 Chemistry 59 590 H

Me H [399] Chemistry 63 Chemistry 64 591 I

Me H 144 Chemistry 68 Chemistry 69 592 I

Me H >250 Chemistry 73 Chemistry 74 593 I

Me H 192 Chemistry 78 Chemistry 79 594 I

Me H 212 Chemistry 83 Chemistry 84 595 I

Me H >250 Chemistry 88 Chemistry 89 596 I

Me H [466] Chemistry 93 Chemistry 94 597 I

Me H >250 Chemistry 98 Chemistry 99 598 Chemistry 102

Me H [227] Chemistry 103 H 599 Chemistry 107

Me H [255] Chemistry 108 H 600 Chemistry 112

Me H [244] Chemistry 113 H 601 Chemistry 117

Me H [291]] Chemistry 118 H 602 I

Me H [508] Chemistry 123 Et 603 I

Me H [427] Chemistry 128 Et 604 I

Me H [429] Chemistry 133 Et 605 I

Me H 178 Chemistry 138 Chemistry 139 606 I

Me H 120 Chemistry 143 Chemistry 144 607 I

Me H >250 Chemistry 148 Chemistry 149 608 I

Me H [437] Chemistry 153 Chemistry 154 609 I

Me H [439] Chemistry 158 Chemistry 159 610 I

Me H [426] Chemistry 163 Chemistry 164 611 I

Me H >250 Chemistry 168 Chemistry 169

612 H

Me H [302] Chemistry 173 CO2Et 613 Br

Me H [381] Chemistry 178 CO2Et 614 Br

Me H [338, 340] Chemistry 183 CH2OH 615 Br

Me H Chemistry 188 CH2Cl 616 Br

Me H >250 Chemistry 193 Chemistry 194 617 I

Me H >250 Chemistry 198 Chemistry 199 618 I

Me H [451] Chemistry 203 Chemistry 204 619 I

Me H [513] Chemistry 508 Chemistry 209 620 I

Me H [639] Chemistry 213 Chemistry 214 621 I

Me H [456] Chemistry 218 Chemistry 219 622 I

Me H [582] Chemistry 223 Chemistry 224 623 I

Me H [428] Chemistry 228 CH2CH2CO2H 624 I

Me H [554] Chemistry 233 CH2CH2CO2H 626 I

Me H [529] Chemistry 238 Chemistry 239 626 I

Me H [453] Chemistry 243 Chemistry 244 627 I

Me H [481] Chemistry 248 Chemistry 249 628 I

Me H [541] Chemistry 253 Chemistry 254 629 I

Me H [510] CHemistry 258 Chemistry 259 630 I

Me H [483] Chemistry 263 Chemistry 264 631 I

Me H [478] Chemistry 268 Chemistry 269 632 I

Me H [492] Chemistry 273 Chemistry 274 633 I

Me H [586] Chemistry 278 Chemistry 279 634 I

Me H [493] Chemistry 283 Chemistry 284 635 I

Me H [536] Chemistry 288 Chemistry 289 636 I

Me H [511] Chemistry 293 Chemistry 294 637 I

Me H [523] Chemistry 298 Chemistry 299 638 I

Me H [508] Chemistry 303 Chemistry 304 639 I

Me H [584] Chemistry 308 Chemistry 309 640 I

Me H [571] Chemistry 313 Chemistry 314 641 I

Me H [484] Chemistry 318 Et 642 I

Me H [498] Chemistry 323 Et 643 I

Me H [510] Chemistry 328 Et 644 I

Me H [545] Chemistry 333 Et 645 I

Me H [514] Chemistry 338 Et 646 I

Me H [546] Chemistry 343 Et 647 I

Me H [497] Chemistry 348 Et 648 I

Me H >250 Chemistry 353 Chemistry 354 649 I

Me H 165 Chemistry 358 Chemistry 359 650 I

Me H 181 Chemistry 363 Chemistry 364 651 I

Me H [497] Chemistry 368 Et 652 I

Me H [515] Chemistry 373 Et 653 I

Me H [443] Chemistry 378 NHCO2Et 654 I

Me H [371] Chemistry 383 Et 655 H

Me H [245] Chemistry 388 Et 656 I

Me H [386] Chemistry 393 Et 657 I

Me H [401] Chemistry 398 Et 658 I

Me H [386] Chemistry 403 Et 659 I

Me H [506] Chemistry 408 Et 660 Br

Me H >250 Chemistry 413 Chemistry 414 661 Br

Me H >250 Chemistry 418 Chemistry 419 662 I

Me H >250 Chemistry 423 Chemistry 424 663 I

Me H [552] Chemistry 428 Chemistry 429 664 I

Me H [483] Chemistry 433 Chemistry 434 665 I

Me H [533] Chemistry 438 Chemistry 439 666 I

Me H [559] Chemistry 443 Chemistry 444 667 I

Me H [516] Chemistry 448 Chemistry 449 668 I

Me H [516] Chemistry 453 Chemistry 454 669 I

Me H [505] Chemistry 458 Chemistry 459 670 I

Me H [497] Chemistry 463 Chemistry 464 671 I

Me H [513] Chemistry 468 Chemistry 469 672 I

Me H [588] Chemistry 473 Chemistry 474 673 I

Me H [558] Chemistry 478 Chemistry 479 674 I

Me H [465] CHemistry 483 Chemistry 484 675 I

Me H [559] Chemistry 488 Chemistry 489 676 I

Me H [521] Chemistry 493 Chemistry 494 677 I

Me H [525] Chemistry 498 Chemistry 499 678 I

Me H >250 CHemistry 503 Chemistry 504 679 I

Me H >250 Chemistry 508 Chemistry 509 680 I

Me H >250 Chemistry 513 Chemistry 514 681 H

Me H [392] Chemistry 518 CO2Et 682 I

Me H [440] Chemistry 523 Et 683 I

Me H [492] Chemistry 528 Et 684 I

Me H [486] Chemistry 533 Et 685 I

Me H [412] Chemistry 538 Et 686 I

Me H [414] Chemistry 543 Et 687 I

Me H [398] Chemistry 548 Et 688 H

Me H [272] Chemistry 553 Et 689 CO2Et

Me H [344] Chemistry 558 Et 690 H

Me H [272] Chemistry 563 Et 691 I

Me H [471] Chemistry 568 Chemistry 569 692 I

Me H [531] Chemistry 573 Et 693 I

Me H [468] Chemistry 578 Chemistry 579 694 I

Me H [572] Chemistry 583 Chemistry 584 695 I

Me H [544] Chemistry 588 Chemistry 589 696 I

Me H [531] Chemistry 593 Chemistry 594 697 I

Me H [482] Chemistry 598 Chemistry 599 698 I

Me H [557] Chemistry 603 Chemistry 604 699 I

Me H [598, 600, 602] Chemistry 608 Chemistry 609 700 I

Me H [548] Chemistry 613 Chemistry 614 701 I

Me H [496] Chemistry 618 Chemistry 619 702 I

Me H [532] Chemistry 623 Chemistry 624 703 I

Me H [544] Chemistry 628 Chemistry 629 704 I

Me H >250 Chemistry 633 Chemistry 634 705 I

Me H [530] Chemistry 638 Chemistry 639 706 I

Me H [450] Chemistry 643 Chemistry 644 707 I

Me H [542, 544] Chemistry 648 Chemistry 649 708 I

Me H [514, 516] Chemistry 653 Chemistry 654 709 I

Me H [528, 530] Chemistry 658 Chemistry 659 710 I

Me H [513] Chemistry 663 Chemistry 664 711 I

Me H [438] Chemistry 668 Chemistry 669 712 I

Me H [451] Chemistry 673 Chemistry 674 713 I

Me H [437] Chemistry 678 Chemistry 679 714 I

Me H [465] Chemistry 683 Chemistry 684 715 I

Me H [513] Chemistry 688 Chemistry 689 716 I

Me H [530] Chemistry 693 Chemistry 694 717 I

Me H [512] Chemistry 698 Chemistry 699 718 I

Me H [450] Chemistry 703 Chemistry 704 719 I

Me H [466] Chemistry 708 Chemistry 709 720 I

Me H [512] Chemistry 713 Chemistry 714 721 I

Me H [464] Chemistry 718 Chemistry 719 722 I

Me H [478] Chemistry 723 Chemistry 724 723 I

Me H [450] Chemistry 728 Chemistry 729 724 I

Me H [526] Chemistry 733 Chemistry 734 725 I

Me H [537] Chemistry 738 Chemistry 739 726 I

Me H [537] Chemistry 743 Chemistry 744 727 I

Me H >250 Chemistry 748 Chemistry 749 728 I

Me H 164 Chemistry 753 Chemistry 754 729 H

Me H [254] Chemistry 758 Et 730 I

Me H [464, 466] Chemistry 763 Et 731 H

Me H [338, 340] Chemistry 768 Et 732 H

Me H [285] Chemistry 773 Et 733 I

Me H [450, 451] Chemistry 778 Et 734 I

Me H [371] Chemistry 783 NH2 735 I

Me H [475] Chemistry 788 Chemistry 789 736 I

Me H [491] Chemistry 793 Chemistry 794 737 I

Me H [399] Chemistry 798 NMe2 738 CO2Et

Me H [428] Chemistry 803 Et 739 I

Me H [461] Chemistry 808 Chemistry 809 740 I

Me H 248 Chemistry 813 Chemistry 814 741 I

Me H >250 Chemistry 818 Chemistry 819 742 I

Me H [486] Chemistry 823 Chemistry 824 743 I

Me H [504, 506, 508] Chemistry 828 Chemistry 829 744 I

Me H [513] Chemistry 833 Chemistry 834 745 I

Me H [562] Chemistry 838 Chemistry 839 746 I

Me H [563] Chemistry 843 Chemistry 844 747 I

Me H [527] Chemistry 848 Chemistry 849 748 I

Me H [563, 565] Chemistry 853 Chemistry 854 749 I

Me H [486] Chemistry 858 Chemistry 859 750 I

Me H [515] Chemistry 863 Chemistry 864 751 I

Me H [500] Chemistry 868 Chemistry 869 752 I

Me H [499] Chemistry 873 Chemistry 874 753 I

Me H [514] Chemistry 878 Chemistry 879 754 I

Me H >250 Chemistry 883 Chemistry 884 755 I

Me H [466] Chemistry 888 Et 756 I

Me H [478] Chemistry 893 Chemistry 894 757 I

Me H >250 Chemistry 898 Chemistry 899 758 I

Me H >250 Chemistry 903 Chemistry 904 759 I

Me H 213 Chemistry 908 Chemistry 909 760 I

Me H 207 Chemistry 913 Chemistry 914 761 I

Me H >250 Chemistry 918 Chemistry 919 762 I

Me H [437] Chemistry 923 Et 763 I

Me H [458] Chemistry 928 Et 764 Vinyl

Me H [321] Chemistry 933 Et 765 H

Me H [286] Chemistry 938 Et 766 I

Me H [429] Chemistry 943 Et 767 H

Me H [284] Chemistry 948 Et 768 CO2Et

Me H [388] Chemistry 953 Et 769 H

Me H [316] Chemistry 958 Et 770 I

Me H [442] Chemistry 963 Et 771 CO2Et

Me H [380, 382] Chemistry 968 Et 772 H

Me H [308, 310] Chemistry 973 Et 773 I

Me H >250 Chemistry 978 Chemistry 979 774 I

Me H [481] Chemistry 983 Chemistry 984 775 I

Me H [545] Chemistry 988 Chemistry 989 776 I

Me H [476] Chemistry 993 Chemistry 994 777 I

Me H [484] Chemistry 998 Chemistry 999 778 I

Me H [588] Chemistry 1003 Chemistry 1004 779 I

Me H [560] Chemistry 1008 Chemistry 1009 780 I

Me H [547] Chemistry 1013 Chemistry 1014 781 I

Me H [591] Chemistry 1018 Chemistry 1019 782 I

Me H [580] Chemistry 1023 Chemistry 1024 783 I

Me H [546] Chemistry 1028 Chemistry 1029 784 I

Me H [574] Chemistry 1033 Chemistry 1034 785 I

Me H [614, 616, 618] Chemistry 1038 Chemistry 1039 786 I

Me H [564] Chemistry 1043 Chemistry 1044 787 I

Me H [548] Chemistry 1048 Chemistry 1049 788 I

Me H [552] Chemistry 1053 Chemistry 1054 789 I

Me H [560] Chemistry 1058 Chemistry 1059 790 I

Me H [586] Chemistry 1063 Chemistry 1064 791 I

Me H [530, 532] Chemistry 1068 Chemistry 1069 792 I

Me H [604] Chemistry 1073 Chemistry 1074 793 I

Me H [580] Chemistry 1078 Chemistry 1079 794 I

Me H [493] Chemistry 1083 Chemistry 1084 795 H

Me H [260] Chemistry 1088 CH2OH 796 H

Me H Chemistry 1093 CH2Cl 797 H

Me H >250 Chemistry 1098 Chemistry 1099 798 I

Me H 245 Chemistry 1103 Chemistry 1104 799 I

Me H >250 Chemistry 1108 Chemistry 1109 800 I

Me H 232 Chemistry 1113 Chemistry 1114 801 I

Me H 224 Chemistry 1118 Chemistry 1119 802 I

Me H 184 Chemistry 1123 Chemistry 1124 803 I

me H >250 Chemistry 1128 Chemistry 1129 804 I

Me H >250 Chemistry 1133 Chemistry 1134 805 I

Me H >250 Chemistry 1138 Chemistry 1139 806 I

Me H >250 Chemistry 1143 Chemistry 1144 807 I

Me H 250 Chemistry 1148 Chemistry 1149 808 I

Me H 198 Chemistry 1153 Chemistry 1154 809 NO2

Me H [363] Chemistry 1158 CO2Et 810 NH2

Me H [317] Chemistry 1163 CO2Et 811 NMe2

Me H [361] Chemistry 1168 CO2Et 812 NMe2

Me H 146 Chemistry 1173 CH2OH 813 NMe2

Me H [337] Chemistry 1178 CH2Cl 814 NMe2

Me H 178 Chemistry 1183 Chemistry 1184 815 NMe2

Me H 168 Chemistry 1188 Chemistry 1189 816 I

Me H [493] Chemistry 1193 Chemistry 1194 817 I

Me H [493] Chemistry 1198 Chemistry 1199 818 I

Me H >250 Chemistry 1203 Chemistry 1204 819 I

Me H >250 Chemistry 1208 Chemistry 1209 820 I

Me H [509] Chemistry 1213 Chemistry 1214 821 I

Me H >250 Chemistry 1218 Chemistry 1219 822 I

Me H >250 Chemistry 1223 Chemistry 1224 823 I

Me H >250 Chemistry 1228 Chemistry 1229 824 I

Me H >250 Chemistry 1233 Chemistry 1234 825 I

Me H >250 Chemistry 1238 Chemistry 1239

A rapid, sensitive and automated assay procedure was used for the in vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cell line, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer, (1985), 36, 445–451) to be highly susceptible to and permissive for HIV infection, served as the target cell line. Inhibition of the HIV-induced cytopathic effect was used as the end point. The viability of both HIV- and mock-infected cells was assessed spectrophotometrically via the in situ reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The 50% cytotoxic concentration (CC₅₀ in μM) was defined as the concentration of compound that reduced the absorbance of the mock-infected control sample by 50%. The percent protection achieved by the compound in HIV-infected cells was calculated by the following formula:

$\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}$ expressed in %, whereby (OD_(T))_(HIV) is the optical density measured with a given concentration of the test compound in HIV-infected cells; (OD_(C))_(HIV) is the optical density measured for the control untreated HIV-infected cells; (OD_(C))_(MOCK) is the optical density measured for the control untreated mock-infected cells; all optical density values were determined at 540 nm. The dose achieving 50% protection according to the above formula was defined as the 50% inhibitory concentration (IC₅₀ in μM). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index (SI). The compounds of formula (I) were shown to inhibit HIV-1 effectively. Particular IC₅₀, CC₅₀ and SI values are listed in Table 2 hereinbelow.

TABLE 2 N° IC50(μm) c SI c CC50(μm) 242 0,0006 > 158489 > 100 255 0,0006 > 15849 > 10 684 0,0008 > 125893 > 100 43 0,0010 10000 10 264 0,0010 > 10000 > 10 470 0,0010 12589 13 483 0,0010 > 100000 > 100 551 0,0010 12589 13 124 0,0013 > 7943 > 10 249 0,0013 > 25119 > 32 298 0,0013 > 7943 > 10 326 0,0013 7943 10 375 0,0013 > 79433 > 100 589 0,0013 > 7943 > 10 606 0,0013 15849 20 133 0,0016 > 6310 > 10 241 0,0016 > 63096 > 100 253 0,0016 > 6310 > 10 306 0,0016 > 19953 > 32 328 0,0016 > 63096 > 100 370 0,0016 > 63096 > 100 662 0,0016 > 63096 > 100 426 0,0016 39811 63 46 0,0020 > 50119 > 100 105 0,0020 > 5012 > 10 234 0,0020 5012 10 254 0,0020 > 15849 > 32 256 0,0020 > 5012 > 10 272 0,0020 12589 25 284 0,0020 > 5012 > 10 296 0,0020 12589 25 319 0,0020 > 50119 > 100 574 0,0020 > 50119 > 100 618 0,0020 25119 50 650 0,0020 > 50119 > 100 83 0,0025 3162 8 88 0,0025 > 39811 > 100 108 0,0025 19953 50 109 0,0025 12589 32 115 0,0025 3162 8 277 0,0025 > 39811 > 100 286 0,0025 > 12589 > 32 299 0,0025 32 0 713 0,0025 > 39811 > 100 45 0,0032 > 31623 > 100 85 0,0032 > 31623 > 100 86 0,0032 > 31623 > 100 231 0,0032 3162 10 409 0,0032 12589 40 244 0,0040 > 25119 > 100 297 0,0040 > 7943 > 32 250 0,0050 5012 25 257 0,0050 > 6310 > 32 307 0,0050 > 6310 > 32 324 0,0050 6310 32 81 0,0063 1995 13 92 0,0063 > 5012 > 32 140 0,0063 > 1585 > 10 143 0,0063 > 1585 > 10 217 0,0063 > 1585 > 10 221 0,0063 > 3162 > 20 230 0,0063 1259 8 232 0,0063 > 5012 > 32 245 0,0063 > 15849 > 100 309 0,0063 1585 10 321 0,0063 > 15849 > 100 322 0,0063 > 15849 > 100 547 0,0063 > 15849 > 100 31 0,0079 > 12589 > 100 218 0,0079 > 1259 > 10 222 0,0079 251 2 700 0,0079 > 1000 > 8 314 0,0079 > 3981 > 32 701 0,0100 6310 63 8 0,0100 > 10000 > 100 99 0,0100 > 10000 > 100 121 0,0100 > 10000 > 100 219 0,0100 > 3162 > 32 233 0,0100 > 1000 > 10 694 0,0100 39811 63 280 0,0100 2512 25 696 0,0158 > 2512 > 40 

1. Compounds of formula (I)

the N-oxides, the pharmaceutically acceptable addition salts, the quaternary amines and stereochemically isomeric forms thereof, wherein Y is O or S; Q is halo; X is a bivalent radical of formula —(CH₂)_(p—)  (a-1) or —(CH₂)_(q)-Z-(CH₂)_(r—)  (a-2); wherein p is an integer of value 1 to 5; q is an integer of value 0 to 5; r is an integer of value 0 to 5; Z is O, S, NR⁷, C(═O), S(═O), S(═O)₂, CHOR¹³, CH═CH, CH(NR⁷R⁸) or CF₂; and wherein each hydrogen atom may be replaced by C₁₋₄alkyl or hydroxyC₁₋₄alkyl; R¹ is C₃₋₆cycloalkyl, C₂₋₆alkenyl or aryl; R² is selected from hydrogen; formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or di(C₁₋₄alkyl)amino; formylamino; mercapto(C₁₋₆)alkyl; hydrazino; R^(5a)R^(6a)N—C(═O—; R⁹—N═C(R¹⁰)—; C₂₋₆alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, di(C₁₋₆alkyl)carbamoyl, [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](C₁₋₄alkyl)carbamoyl, [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](arylC₁₋₄alkyl)carbamoyl, di(C₁₋₄alkyloxy)(C₁₋₄alkyl)carbamoyl, (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)aminoC₁₋₆alkyl, N-hydroxy-imino, aryl, Het², Het²carboxamido, Het²(C₁₋₆alkyl)carbamoyl; C₂₋₆alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₁₋₆alkyloxy; hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy, mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl; Het²carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl; aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or di(aryl)amino; Het²; Het²oxy; Het²thio; Het²C₁₋₆alkyloxy; Het²C₁₋₆alkylthio; Het²SO₂; Het²SO; mono- or di(Het²)amino; C₃₋₆cycloalkyl; C₃₋₆cycloalkyloxy; C₃₋₆cycloalkylthio; C₁₋₆alkylthio; hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, carboxyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkycarbamoylC₁₋₄alkylthio, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylthio C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het², aryloxy, arylthio, arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het²C₁₋₆alkyloxy, Het²C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)₂-oxy, amino, mono- or di(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)aminoC₁₋₆alkylthio, [di(C₁₋₆alkyl)amino(C₁₋₆alkyl)](C₁₋₆alkyl)amino, di(cyanoC₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or di(Het²C₁₋₄alkyl)amino, (Het²C₁₋₄alkyl)(C₁₋₄alkyl)amino, (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)amino, C₃₋₆cycloalkylthio, R¹¹—(C═O)—NH—, R¹²—NH—(C═O)—NH—, R¹⁴—S(═O)₂—NH—, C₁₋₆alkyl-P(O—R¹⁵)2=O, C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O or a radical of formula

 with A₁ being CH or N, and A₂ being CH₂, NR¹³, S or O, provided that when A₁ is CH then A₂ is other than CH₂, said radical (c-1), (c-2) and (c-3) being optionally substituted with one or two substituents each independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkyloxy, hydroxy C₁₋₄alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₄alkyl, aminoC₁₋₆alkyl, C₁₋₄alkylcarbonyl, arylcarbonyl, aryl, Het¹, Het¹—(C═O)—, hydroxy, cyano, C₁₋₄alkylcyano, CONR¹⁶R¹⁷ with R¹⁶ and R¹⁷ being independently H or alkyl, mono or di(C₁₋₄alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4-phenyl; R³ is selected from hydrogen; halo; formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or di(C₁₋₄alkyl)amino; formylamino; mercapto(C₁₋₆)alkyl; hydrazino; R^(5a)R^(6a)N—C(═O)—; R⁹—N═C(R¹⁰)—; C₂₋₆alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, di(C₁₋₄alkyl)carbamoyl, [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](CC₁₋₄alkyl)carbamoyl, [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](arylC₁₋₄alkyl)carbamoyl, di(C₁₋₄alkyloxy)(C₁₋₄alkyl)carbamoyl, (cyanoC₁₋₆alkyl)(CC₁₋₆alkyl)aminoC₁₋₆alkyl, N-hydroxy-imino, aryl, Het², Het²carboxamido, Het²(C₁₋₆alkyl)carbamoyl; C₂₋₆alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₁₋₆alkyloxy; hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl; Het²carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl; aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or di(aryl)amino; Het²; Het²oxy; Het²thio; Het²C₁₋₆alkyloxy; Het²C₁₋₆alkylthio; Het²SO₂; Het²SO; mono- or di(Het²)amino; C₃₋₆cycloalkyl; C₃₋₆cycloalkyloxy; C₃₋₆cycloalkylthio; C₁₋₆alkylthio; hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, carboxyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkycarbamoylC₁₋₄alkylthio, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylthio, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het², aryloxy, arylthio, arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het²C₁₋₆alkyloxy, Het²C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)₂-oxy, amino, mono- or di(C₁₋₆alkyl)amino, di(C₁₋₆alkyl)aminoC₁₋₆alkylthio, [di(C₁₋₆alkyl)amino(C₁₋₆alkyl)](C₁₋₆alkyl)amino, di(cyanoC₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or di(Het²C₁₋₄alkyl)amino, (Het²C₁₋₄alkyl)(C₁₋₄alkyl)amino, (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)amino, C₃₋₆cycloalkylthio, R¹¹—(C═O)—NH—, R¹²—NH—(C═O)—NH—, R¹⁴—S(═O)₂—NH—, C₁₋₆alkyl-P(O—R¹⁵)2=O, C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O or a radical of formula

 with A₁ being CH or N, and A₂ being CH₂, NR¹³, S or O, provided that when A₁ is CH then A₂ is other than CH₂, said radical (c-1), (c-2) and (c-3) being optionally substituted with one or two substituents each independently selected from H, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₄alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₄alkyl, aminoC₁₋₆alkyl, C₁₋₄alkylcarbonyl, arylcarbonyl, aryl, Het¹, Het¹-(C═O)—, hydroxy, cyano, C₁₋₄alkylcyano, CONR¹⁶R¹⁷ with R¹⁶ and R¹⁷ being independently H or alkyl, mono or di(C₁₋₄alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4-phenyl; or R² and R³ may be taken together to form a bivalent radical of formula —(CH₂)_(t)—CH₂-A₃-CH₂—  (d-1) with t being an integer of 0, 1 or 2 and A₃ being CH₂, O, S, NR^(7a) or N[C(═O)R^(8a)] and wherein each hydrogen in said formula (d-1) may be substituted with halo, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl, haloC₁₋₄alkylcarbonyl or arylcarbonyl; R⁴ is hydrogen; R^(5a) and R^(6a) each independently are hydrogen; C₁₋₄alkyl optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkylthio, amino, mono- or di(C₁₋₄alkyl)amino or a radical of formula

 with A₅ and A₆ each independently being CH₂, NR¹³ or O; R⁷, R^(7a) and R^(7b) each independently are hydrogen, formyl or C₁₋₄alkyl; R⁸, R^(8a) and R^(8b) each independently are hydrogen or C₁₋₄alkyl; R⁹ is hydrogen, hydroxy, C₁₋₄alkyloxy, carboxylC₁₋₄alkyloxy, C₁₋₄alkyloxycarbonylC₁₋₄alkyloxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy or arylC₁₋₄alkyloxy; R¹⁰ is hydrogen, carboxyl or C₁₋₄alkyl; R¹¹ is hydrogen; C₁₋₄alkyl optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkyl-S(═O)₂—, aryl or Het³; C₁₋₄alkyloxy; C₂₋₄alkenyl; arylC₂₋₄alkenyl; Het³C₂₋₄alkenyl; C₂₋₄alkynyl; Het³C₂₋₄alkynyl, arylC₂₋₄alkynyl; C₃₋₆cycloalkyl; aryl; naphthyl or Het³; R¹² is C₁₋₄alkyl, arylC₁₋₄alkyl, aryl, arylcarbonyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl or C₁₋₄alkyloxycarbonylC₁₋₄alkyl; R¹³ is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl; R¹⁴ is C₁₋₄alkyl optionally substituted with aryl or Het⁴; polyhaloC₁₋₄alkyl or C₂₋₄alkenyl optionally substituted with aryl or Het⁴; R¹⁵ is C₁₋₄alkyl; Het¹ and Het² each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyrimidinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, morpholinyl, thiomorpholinyl triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indazolyl, benzodioxanyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, imidazopyridinyl, dihydropyrrolyl or dihydroisoxazolyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from O, S, halo, formyl, amino, hydroxy, cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, carboxyC₁₋₄alkyl, carbamoylC₁₋₄alkyl, carbamoylC₁₋₄alkoxy, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxyC₁₋₄alkyl, cyanoC₁₋₄alkyl, di(C₁₋₄alkyl)aminoC₁₋₄alkyl, —OCONH₂, C₁₋₄alkoxyC₁₋₄alkyl, aryl, Het²C₁₋₄alkyl, polyhaloC₁₋₄alkyl, C₃₋₆cycloalkyl or arylC₂₋₆alkenyl; Het³ is a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl or a radical of formula

 with A₇ or A₈ each independently being selected from CH₂ or O; each of said monocyclic or bicyclic heterocycles may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; Het⁴ is a monocyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; Het⁵ is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl, oxazolyl, tetrazolyl, piperidinyl, morpholinyl or pyrrolidinyl; aryl is phenyl optionally substituted with one, two or three substituents each independently selected from halo; hydroxy; carboxyl; cyano; formyl; acetyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; mono- or di(C₁₋₄alkyl)aminocarbonylamino; C₁₋₄alkyl-S(═O)₂—NH—; Het⁵(═S)—S—C₁₋₄alkyl; C₁₋₆alkyloxy; sulfamoyl; C₁₋₄alkyl)sulfamoyl; arylsulfamoyl; Het²sulfamoyl; O—P═OR¹⁵; C₁₋₆alkyl optionally substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₂₋₆alkenyloxy, C₁₋₆alkylcarbonyloxy, C₁₋₆alkyloxycarbonylthio, N-hydroxyimino, phenyl or Het⁵; C₂₋₆alkenyl optionally substituted with halo, hydroxy, cyano, nitro, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; C₂₋₆alkynyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; phenyl; phenyloxy; phenyl(C₁₋₄alkyl)thioC₁₋₄alkyl; (C₃₋₆)cyclohexylthioC₁₋₄alkyl or isoxazolinyl optionally substituted by C₁₋₄alkyloxycarbonyl or morpholinylC₁₋₄alkyl provided that 3-iodo-6-methyl-4-phenoxy-2(1H)-pyridinone is not included.
 2. A compound according to claim 1 wherein Q is halo; X is a bivalent radical of formula —(CH₂)_(p)—  (a-1) or —(CH₂)_(q)-Z-(CH₂)_(r)—  (a-2); wherein p is an integer of value 1 to 5; q is an integer of value 0 to 5; r is an integer of value 0 to 5; Z is O, S, NR⁷, C(═O), S(═O), S(═O)₂, CHOR¹³, CH═CH, CH(NR⁷R⁸) or CF₂; and wherein each hydrogen atom may be replaced by C₁₋₄alkyl or hydroxyC₁₋₄alkyl; R¹ is C₃₋₆cycloalkyl; or aryl; R² is selected from hydrogen; formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or di(C₁₋₄alkyl)amino; formylamino; R^(5a)R^(6a)N—C(═O)—; R⁹—N═C(R¹⁰)—; C₂₋₆alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₂₋₆alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₁₋₆alkyloxy; hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl; Het²carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl; aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or di(aryl)amino; Het²; Het²oxy; Het²thio; Het²C₁₋₆alkyloxy; Het²C₁₋₆alkylthio; mono- or di(Het²)amino; C₃₋₆cycloalkyl; C₃₋₆cycloalkyloxy; C₃₋₆cycloalkylthio; C₁₋₆alkylthio; hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, C₁₋₆alkyloxy, C₁₋₆alkylthio, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het², aryloxy, arylthio, arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het²C₁₋₆alkyloxy, Het²C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)₂-oxy, amino, mono- or di(C₁₋₆alkyl)amino, C₁₋₆alkyloxy-carbonylamino, C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or di(Het²C₁₋₄alkyl)amino, R¹¹—(C═O)—NH—, R¹²—NH—(C═O)—NH—, R¹⁴—S(═O)₂—NH—, C₁₋₆alkyl-P(O—R¹⁵)2=O, C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O or a radical of formula

 with A₁ being CH₂ or N, and A₂ being CH₂, NR¹³, S or O, provided that when A₁ is CH₂ then A₂ is other than CH₂, said radical (c-1) and (c-2) being optionally substituted with one or two substituents each independently selected from H, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxy C₁₋₄alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₄alkyl, aminoC₁₋₆alkyl, carbonyl, hydroxy, cyano, CONR¹⁶R¹⁷ with R¹⁶ and R¹⁷ being independently H or alkyl, mono or di(C₁₋₄alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4-phenyl; R³ is selected from hydrogen; halo; formyl; cyano; azido; hydroxy; oxiranyl; amino; mono- or di(C₁₋₄alkyl)amino; formylamino; mercapto(C₁₋₆)alkyl; hydrazino; R^(5a)R^(6a)N—C(═O)—; R⁹—N═C(R¹⁰)—; C₂₋₆alkenyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, di(C₁₋₄alkyl)carbamoyl, [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](C₁₋₄alkyl)carbamoyl, [di(C₁₋₄alkyl)amino(C₁₋₆alkyl)](arylC₁₋₄alkyl)carbamoyl, di(C₁₋₄alkyloxy)(C₁₋₄alkyl)carbamoyl, (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)aminoC₁₋₆alkyl, N-hydroxy-imino, aryl, Het², Het²carboxamido, Het²(C₁₋₆alkyl)carbamoyl; C₂₋₆alkynyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, formyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, aryl or Het²; C₁₋₆alkyloxy; hydroxyC₁₋₆alkyloxy; aminoC₁₋₆alkyloxy; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkyloxy; C₁₋₆alkylcarbonyl; arylcarbonyl; Het²carbonyl; C₁₋₆alkyloxycarbonyl; C₁₋₆alkylcarbonyloxy; aryl; aryloxy; arylC₁₋₆alkyloxy; arylthio; arylC₁₋₆alkylthio; mono- or di(aryl)amino; Het²; Het²oxy; Het²thio; Het²C₁₋₆alkyloxy; Het²C₁₋₆alkylthio; Het²SO₂; Het²SO; mono- or di(Het²)amino; C₃₋₆cycloalkyl; C₃₋₆cycloalkyloxy; C₃₋₆cycloalkylthio; C₁₋₆alkylthio; hydroxyC₁₋₆alkylthio; aminoC₁₋₆alkylthio; mono- or di(C₁₋₄alkyl)aminoC₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with one or two substituents each independently selected from halo, hydroxy, cyano, carboxyl, C₁₋₆alkyloxy, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkycarbamoylC₁₋₄alkylthio, hydroxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkylthioC₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, aminocarbonyloxy, mono- or di(C₁₋₄alkyl)aminocarbonyloxy, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆alkyloxy, C₁₋₆alkyloxycarbonylC₁₋₆alkylthio, aryl, Het², aryloxy, arylthio, arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio, Het²C₁₋₆alkyloxy, Het²C₁₋₆alkylthio, C₁₋₆alkyl-S(═O)₂-oxy, amino, mono- or di(C₁₋₆amino, di(C₁₋₆alkyl)aminoC₁₋₆alkylthio, [di(C₁₋₆alkyl)amino(C₁₋₆alkyl)](C₁₋₆alkyl)amino, di(cyanoC₁₋₆alkyl)amino, C₁₋₆alkyloxycarbonylamino, C₁₋₆alkyloxyC₁₋₆alkylcarbonylamino, mono- or di(aryl)amino, mono- or di(arylC₁₋₄alkyl)amino, mono- or di(C₁₋₄alkyloxyC₁₋₄alkyl)amino, mono- or di(CC₁₋₄alkylthioC₁₋₄alkyl)amino, mono- or di(Het²CC₁₋₄alkyl)amino, (Het²C₁₋₄alkyl)(C₁₋₄alkyl)amino, (cyanoC₁₋₆alkyl)(C₁₋₆alkyl)amino, C₃₋₆cycloalkylthio, R¹¹—(C═O)—NH—, R¹²—NH—(C═O)—NH—, R¹⁴—S(═O)₂—NH—, C₁₋₆alkyl-P(O—R¹⁵)2=O, C₁₋₆alkyl-P(O—C₁₋₆alkyl-O)═O or a radical of formula

 with A₁ being CH or N, and A₂ being CH₂, NR¹³, S or O, provided that when A₁ is CH then A₂ is other than CH₂, said radical (c-1), (c-2) and (c-3) being optionally substituted with one or two substituents each independently selected from H, C₁₋₆alkyl, C₁₋₆alkyloxy, hydroxyC₁₋₄alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxycarbonylC₁₋₄alkyl, aminoC₁₋₆alkyl, C₁₋₄alkylcarbonyl, arylcarbonyl, aryl, Het¹, Het¹-(C═O)—, hydroxy, cyano, C₁₋₄alkylcyano, CONR¹⁶R¹⁷ with R¹⁶ and R¹⁷ being independently H or alkyl, mono or di(C₁₋₄alkyl)aminoalkyl, 4-hydroxy-4-phenyl or 4-cyano-4-phenyl; or R² and R³ may be taken together to form a bivalent radical of formula —(CH₂)_(t)—CH₂-A₃-CH₂—  (d-1) with t being an integer of 0, 1 or 2 and A₃ being CH₂, O, S, NR^(7a) or N[C(═O)R^(8a)] and wherein each hydrogen in said formula (d-1) may be substituted with halo, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl, haloC₁₋₄alkylcarbonyl or arylcarbonyl; R⁴ is hydrogen; R^(5a) and R^(6a) each independently are hydrogen; C₁₋₄alkyl optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkylthio, amino, mono- or di(C₁₋₄alkyl)amino or a radical of formula

 with A₅ and A₆ each independently being CH₂, NR¹³ or O; R⁷, R^(7a) and R^(7b) each independently are hydrogen, formyl or C₁₋₄alkyl; R⁸, R^(8a) and R^(8b) each independently are hydrogen or C₁₋₄alkyl; R⁹ is hydrogen, hydroxy, C₁₋₄alkyloxy, carboxylC₁₋₄alkyloxy, C₁₋₄alkyloxycarbonylC₁₋₄alkyloxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy or arylC₁₋₄alkyloxy; R¹⁰ is hydrogen, carboxyl or C₁₋₄alkyl; R¹¹ is hydrogen; C₁₋₄alkyl optionally substituted with cyano, C₁₋₄alkyloxy, C₁₋₄alkyl-S(═O)₂—, aryl or Het³; C₁₋₄alkyloxy; C₂₋₄alkenyl; arylC₂₋₄alkenyl; Het³C₂₋₄alkenyl; C₂₋₄alkynyl; Het³C₂₋₄alkynyl, arylC₂₋₄alkynyl; C₃₋₆cycloalkyl; aryl; naphthyl or Het³; R¹² is C₁₋₄alkyl, arylC₁₋₄alkyl, aryl, arylcarbonyl, C₁₋₄alkylcarbonyl, C₁₋₄alkyloxycarbonyl or C₁₋₄alkyloxycarbonylC₁₋₄alkyl; R¹³ is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl; R¹⁴ is C₁₋₄alkyl optionally substituted with aryl or Het⁴; polyhaloC₁₋₄alkyl or C₂₋₄alkenyl optionally substituted with aryl or Het⁴; R¹⁵ is C₁₋₄ alkyl; Het¹ and Het² each independently are a heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl or 2-oxo-1,2-dihydro-quinolinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; Het³ is a monocyclic or bicyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, 2-oxo-1,2-dihydro-quinolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, hexahydropyrimidinyl, piperazinyl, hexahydropyridazinyl or a radical of formula

 with A₇ or A₈ each independently being selected from CH₂ or O; each of said monocyclic or bicyclic heterocycles may optionally be substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; Het⁴ is a monocyclic heterocycle selected from pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said heterocycle optionally being substituted with one, two or three substituents each independently selected from halo, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyl or polyhaloC₁₋₄alkyl; Het⁵ is pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, pyrrolyl, thienyl, furanyl, imidazolyl, thiazolyl or oxazolyl; aryl is phenyl optionally substituted with one, two or three substituents each independently selected from halo; hydroxy; carboxyl; cyano; formyl; nitro; amino; mono- or di(C₁₋₄alkyl)amino; C₁₋₄alkylcarbonylamino; mono- or di(C₁₋₄alkyl)aminocarbonylamino; C₁₋₄alkyl-S(═O)₂—NH—; C₁₋₆alkyloxy; C₁₋₆alkyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; C₂₋₆alkenyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; C₂₋₆alkynyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; phenyl or phenyloxy.
 3. A compound according to claim 1 wherein Q is halo; X is (a-2) with q and r being 0 and Z being O, S or SO; R₁ is phenyl optionally substituted with one, two or three substituents each independently selected from halo; hydroxy; carboxyl; cyano; formyl; nitro; amino; mono- or di(C₁₋₆alkyl)amino; C₁₋₄alkylcarbonylamino; mono- or di(C₁₋₄alkyl)aminocarbonylamino; C₁₋₄alkyl-S(O)₂—NH—; C₁₋₆alkyloxy; C₁₋₆alkyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkyloxyC₁₋₆alkyloxy, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; C₂₋₆alkenyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di(C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; C₁₋₆alkynyl optionally substituted with halo, hydroxy, cyano, formyl, amino, mono- or di C₁₋₄alkyl)amino, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkylcarbonyloxy, N-hydroxy-imino, phenyl or Het⁵; phenyl or phenyloxy; R₂ is selected from formyl; C₁₋₆alkyloxycarbonylalkyl; Het²; Het²C₁₋₆alkyl; C₁₋₆alkylthio; C₁₋₆alkyl optionally substituted with one or two substituents each independently selected from hydroxy or halo; R₃ is selected from formyl or C₁₋₆alkyl optionally substituted with one or two C₁₋₆alkyloxy; and R₄ is hydrogen.
 4. A compound as according to claim 1 wherein Q is iodo.
 5. A compound according to claim 1 wherein Q is iodo, X—R₁ is a 3,5-dimethylphenylthio or a 3,5-dimethylphenyloxy and R₂ is a hydroxymethyl or a N-morpholinomethyl, or a 3-phenylpropyl or a furan-2-yl-methylthiomethyl.
 6. A compound according to claim 1 wherein Q is iodo, X—R₁ is a 3-(2-cyano-vinyl)-5-iodophenyloxy or 5-bromo-3-(2-cyano-vinyl) and R₂ is ethyl.
 7. A compound according to claim 1 wherein the compounds are listed in the following table; No Y Q X–R1 R2 R3 R4 8 O I

Me H 31 O I

Me H 43 O I

Me H 45 O I

Me H 46 O I

Me H 81 O I

Et Me H 83 O I

Et Me H 85 O Br

Me H 86 O I

Me H 88 O I

Et Me H 92 O I

Me H 99 O I

Me H 105 O I

Et

H 108 O I

Et Me H 109 O I

Et Me H 115 O I

Et Me H 121 O I

Et Me H 124 O I

Me H 133 O I

Et CH2OH H 140 O I

CH═CHCN Me H 143 O I

Me H 217 O I

Et

H 218 O I

Me H 219 O I

Me H 221 O I

H 222 O I

H 232 O I

Me H 233 O I

Me H 241 O I

Me H 242 O I

Me H 244 O I

Me H 245 O I

Me H 249 O I

2-methoxyethyl Me H 250 O I

Me H 253 O I

Me H 254 O I

Me H 255 O I

Me H 256 O I

H H 257 O I

CH2OH Me H 264 O I

2-methoxyethyl Me H 284 O Br

Et Me H 286 O I

Et Me H 296 O I

Et Me H 297 O I

Et Me H 298 O I

Et Me H 299 O I

Et Me H 306 O I

Et Me H 307 O I

Et Me H 309 O I

Et Me H 314 O I

Et H H 319 O I

Et Me H 321 O I

Et Me H 322 O I

Et Me H 326 O I

Et Me H 328 O I OPh Et Me H 370 O I

Me H 375 O I

Me H 426 O I

Et Me H 470 O I

Et Me H 483 O I

Me H 547 O I

Me H 551 O I

Et Me H 574 O I

Me H 589 O I

Me H 606 O I

Me H 618 O I

Me H 650 O I

Me H 662 O I

Me H 684 O I

Et Me H 694 O I

Me H 696 O I

Me H 700 O I

Me H 701 O I

Me H 709 O I

Me H 713 O I

Me H


8. A method for treating subjects suffering from Human Immuno Deficiency Virus infection by administering a therapeutically effective amount of a compound according to claim
 1. 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically active amount of a compound according to claim
 1. 